PT2403832E - N-(hetero)aryl,2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators - Google Patents

Description

ΕΡ2403832Β1

DESCRIPTION

N- (HETERO) ARYL, 2- (HETERO) ARYL-SUBSTITUTED ACETAMIDES FOR USE AS WNT SIGNALING MODULATORS

Technical Field

The present invention relates to compounds and action in the modulation of the Wnt signaling pathway. yes

J.6L

Background The phyllis of the Wnt gene encodes a large class of secreted proteins related to the proto-oncogene Intl / Wnt1 and Drosophila wingless (" Wg "), a homolog of Drosophila Wnt1 (Cadigan et al., (1997) Genes & Development 11: 3286-3305). Wnts are expressed in a variety of tissues and organs and play a major role in many developmental processes, including Drosophila segmentation; development of endoderma in C. elegans; and establishment of member polarity, neural Christian differentiation, kidney morphogenesis, sex determination, and brain development in mammals (Parr, et al. (1994) Curr. Opinion Genetics & Devei 4: 523-528). The Wnt pathway is a master regulator in the development of the animal, both during embryogenesis and in the mature organism (Eastman, et al. (1999) Curr Opin Cell Biol 11: 233-240;

Peifer, et al. (2000) Science 287: 1606-1609).

The Wnt signals are transduced by the Frizzled family (" Fz ") of seven transmembrane domain receptors (Bhanot et al. (1996) Nature 382: 225-230). The ligands of

Wnt binds to Fzd, and in so doing, they served the Disheveled cytoplasmic protein (Dvl-1, 2 and 3 in humans and mice) (Boutros, et al. (1999) Mech De v. 83: 27-37) and 1β2403832β phosphorylate LRP5 / 6. One prevents the signal phosphorylation is thus generated which and degradation of Armadillo / β (beta) - catenin, in turn leading to the stabilization of β-catenii (Perrimon occasioned (1994) Ce11 76: 781-784). This by association of Dvl with ax stabilization is in (Zeng et al. (1997) Cell 90: 181-192), various proteins together catenin, to form the one structural protein that e, including GSK3, APC, CK1, destruction complex d brings and B-! β-catenin. The pathway to the Frizzled protein receptor of the Wingless type (Wnt) involves important regulatory genes that have polymorphisms associated with primary carcinomas. In the course of downstream signaling, cytosolic -catenin accumulates, translocates into the nucleus, and then increases gene expression through complexation with other transcription factors Uthoff et al., Mol Carcinog, 31: 56-62 (2001). In the absence of Wnt signals, free cytosolic β-catenin is incorporated into a complex consisting of Axin, the adenomatous polypeptide coli (APC) gene product, and glycogen ima qumase (03Κ) -3β. Conjugator phosphorylation

Cl. ie

Axina, APC, and β-catenin by 0.8Κ-3β designates β-catenin for the ubiquitin pathway and degradation by proteasomes Uthoff et al., Mol Carcinog, 31: 56-62 (2001); Matsuzawa et al., Mol Cell, 7: 915-926 (2001).

Disheveled (Dvl) is a positive Wnt signaling mediator positioned downstream of the frizzled and upstream β-catenin receptors. GSK-3 phosphorylates several proteins in the Wnt pathway and is instrumental in downstream regulation of β ~. catenin. Mutations in the APC gene are an initiation event for both sporadic and hereditary colorectal tumorigenesis. APC mutants are relevant in tumorigenesis, since the aberrant protein is an integral part of the Wnt signaling cascade. The product of 2β2383832Β1 protein contains several functional domains that act as binding and degradation sites for β-catenin. Mutations occurring in the amino-terminal segment of β-catenin are usually involved in phosphorylation-dependent ubiquitin-mediated degradation and thus stabilize β-catenin. As the stabilized cytoplasmic catenin accumulates, it translocates to the nucleus interacting with the high mobility group Tcf / Lef of transcription factors that modulate the expression of oncogenes such as c-myc.

It is known that Wnt / β-catenin signaling promotes cell survival in various cell types Orford et al., J Cell 155: 1 725-17 (2000); Sat · ai., Journa Chen et al. al., Nat In (1999); Cox et al., Genetics, et al., Immunity, 13: 15-24 (2000); Satoh et al., Nat Genet, 24: 245-250 (2000); Shin et of Biological Chemistry, 274: 2780-2785 (1999); Chen et al., J Cell Biol, 152: 87-96 (2001); Ioannidis et al: 691, 69, (2001). P ã ã ã ã ã ã este P P P P P P P P P P P P 8. 8.. / "185: · ι (2000); Cox > 0)! Biennale et al., J. Biol., 157: 237-229. In addition, it is also known that Wnt oxidation virus is associated with (Polakis et al., Et al., Genetics, 103: 311-320 (2000); or et al., J Cell Biol, 157: 429-440 (zvvz)). aberrant activation of the Wnt signaling pathway is associated with a variety of human cancers, which correlate with overexpression or amplification of c-Myc (Polakis et al. Genes Dev, 14: 1837-1851 (2000); et al., Cell, 103: 311-320 (2000), Brown et al., Breast Cancer Res, 3: 351-355 (2001), He et al., Science, 281: 1509-1512 (1998); Miller et al., Oncogene, 18: 7860-7872 (1999), as one of the cancer cells targets 509-1512 (1998); USA, 95: 8847-8851 colo-rectal (He et al.

Over there. Coste et al. 3 ΕΡ2403832Β1 (1998); Miller et al. , Oncogene, 18: 7860-7872 (1999); You et al., J Cell Biol, 157: 429-440 (2002)).

Thus, a need exists for agents and methods that modulate the Wnt signaling pathway, thereby treating, diagnosing, preventing, and / or ameliorating disorders related to Wnt signaling.

DISCLOSURE OF THE INVENTION The present invention relates to compounds and their use in modulating the Wnt signaling pathway. The present invention is as defined in the claims.

Described herein are compounds having Formula (1) or (2):

ring E is an optionally substituted aryl or heteroaryl; A1 and Az are independently a Ch-heterocycle, quinolinyl, or a heteroaryl selected from:

EP24Q3832B1

wherein any heterocycle of A 1 and A 2 may be optionally substituted with -LC (O) RU; wherein the nitrogen may be optionally oxidized (see, for example, compound 156 of table 1). B is benzothiazolyl, quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 groups R °; X1, X2, ΧΛ and X4 are independently CR7 or N; Y is phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; Z is aryl, C 1-5 heterocycle, or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; each Y and Z are optionally substituted with 1-3 radicals R6; R1 and R2 are independently H or C1-6 alkyl; R2 and R3 are independently H, C1-6 alkyl or halo; R4 is halo, cyano, C1-6 alkoxy, or a C1-6 alkyl optionally substituted with halo, alkoxy or amino; R 6 is hydrogen, halo, -C (O) R 10, -C (O) NR 8 R 9, C 1-6 alkynyl, each of which may optionally be oxo-C (O), n is 1,

Or substituted with halo, amino, hydroxy, alkoxy or cyano; (O) NR 8 R 9, -L-C (O) R 1 G, -L-C (O) O R 10, -L-C (O) NR 8 R 9, -L-S (O) 2 R 10 or -L-S (O) 2 NR 8 R 9; R 'is H, halo, C 1-6 alkoxy, -L-S (O) 2 R 11, cyano, C 1-6 alkoxy,

C1-6 alkyl, optionally substituted with halo, amino, hydroxy, alkoxy or cyano; NRsRy, -L-C (O) R1, -L-n (O) nR8 R9; or -L-S (O) 2 NR 8 R 9; R8 and R9 are independently H, -L-W, or C1-6 alkyl, C2-6 alkenyl or C1-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxy, alkoxy or cyano; or R8 and R9 together with the atoms to which they are attached may form a ring; R1 is H, -L-W, or C1-6 alkyl, C2-5 alkenyl or C2- and alkynyl, each of which may be optionally substituted with halo, amino, hydroxy, alkoxy or cyano; L is a bond or (CR2) 1-4 wherein R is H or C1-6 alkyl; W is C 3 -C 7 cycloalkyl, C 1-6 heterocycle, aryl or heteroaryl; m is 0-4; n is 0-3; and p is 0-2; and the solvates, hydrates, n-oxide derivative or prodrugs thereof.

In the above Formula (1), Y is phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted with 1-2 groups R6. In other examples, Z is phenyl, pyridyl, pyridazine, pyrazidine, pyrazine, piperazinyl, py morpholinyl, pyrazole or 1,2,3,6-tetrahydropyridines of which is optionally substituted with 1-2 g

Also described herein are Formula (3):

Also described herein is Formula (4):

In any of the above Formulas (1), (2), A1 and At are independently morpholinyl, pyrazolinyl, OH-z or a heteroaryl selected from the peridinyl group, each of R6, as were as (3) or (4) compounds as peraphene, ΕΡ2403832Β1

Qtd A and K 'may be the O in which Pc and n are were any heterocycle optionally substituted with - as defined above.

In some examples, the ring E in any of the above Formulas (1), (2), (3) or (4) is phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with R7, wherein R3 is as was defined above. In examples i. i. particularly R * is optionally halogenated.

Also recited herein are compounds of Formula (5): in

is piperazinyl substituted with -C (O) CH 3, R 2

O selected starting at: 8 ΕΡ2403832Β1

R

Ν (R4),

Ν (R 4) n (R 4),.

ου r ο s ο C ο ο;

Ρ = γπ of Χ% X, Χ ~ and X 'is Ν & η q is one of Xs, X6, X 'and XB is N and the others are CR11; Z is a 6-membered heterocycle or a 6-membered neteroaryl, each containing 1-2 heteroatoms of nitrogen and each of which is optionally substituted with 1-2 Rb groups; R1, R2 and R3 are H or C1 -C6 alkyl; R 2 and R 3 are independently hydrogen, C 1 -C 10 -alkoxy, -S (O) 2 R 11, C (O) NR 12, -L-C (O) R 11, -LC (O) wherein R1 is phenyl or C2-6 alkynyl; R1 is C1-6 alkyl, or -L-W; L is a bond or (CR 2) 1-4 wherein R 1 is H or C 1-6 alkyl; W is C 3-7 cycloalkyl; R 'and R11 are independently H, halo, cyano, C1-6 alkoxy, -S (O) 2 R10, or an optionally halogenated C1-6 alkyl; n and n are independently 0-1.

In another embodiment, with reference to Formula 9 ΕΡ2403832Β1 (b), A " is piperazinyl substituted with -C (O) CH 3, R 4,

one of X 1, X 6, X 7 and X 8 is N and the others are CR 11; Z is a 6-membered heterocycle or a 6-membered heteroaryl, each containing 1-2 heteroatoms of nitrogen and each of which is optionally substituted with 1-2 groups R 6; R1, R2 and R3 are H or C1-6 alkyl; R4 and R6 are independently hydrogen, cyano, C1-C6-alkoxy, S (O) 2 R] O, -C (O) NRsR9, -LC (O) R] 0, -L-C (O) OR] 0, optionally substituted with halo, C2-8 alkenyl or C2-6 alkynyl; R18 is C1-6 alkyl or -L-W; L is a bond or (CR2) 1-4 wherein R is H or C1-6 alkyl; W is C3-7 cycloalkyl; R 1 and R 11 are independently H, halo, cyano, C 1-5 alkoxy, -S (O) 2 R 11, or an optionally halogenated C 1-6 alkyl; and m and n are independently 0-2. im algur

In nrrro? The examples, examples, Z in R1J in Formula (5) is C2-6 alkyl. Formula (5) is a heteroaryl of 6 10 ΕΡ2403832Β1 ΕΡ2403832Β1 of nitrogen, or a C4 heteroatoms of nitrogen. X, X and X and X and X are as defined above. In yet other examples, one of X1 and X1 are CR2. are also described in the following section (6):

2, X3 and X4 is selected from N, X6, X7 and X8 is N and the others are CH; X3 Cl from Tsi Θ Cri; Z 1 is selected from phenyl, pyrazinyl, pyridinyl 0: wherein each phenyl, pyrazinyl, wherein R 6; ; R 4 is selected from difluoromethyl, z, and optionally R 1, R 2 and R 3 are selected from the group consisting of pyridyl; pyridinyl or piperazinyl group substituted with a hydroxyl group; m R ° is selected from hydrogen, halo and C (O) RU; wherein R3 is methyl; and R 'is selected from hydrogen, halo, cyano, methyl and trifluoromethyl.

In another example, R 4 and R 5 are independently selected from the group consisting of R 1, R 2, R 3, R 4 and R 5 are each independently selected from the group consisting of: The compounds of formula (I) are prepared from hydrogen, halo, trifluoromethyl, methyl and -C (O) CH 3.

Examples of the compounds described in the present document include: tert -Butyl 4- (5 - (2- [4- (2-methylpyridin-4-yl) phenyl] acetamido} pyridin-2-yl) -1,2 N- (6- (p-fluorophenyl) pyridin-3-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; methoxy-1,3-benzothiazol-2-yl) -2- [4- (pyridin-4-yl) phenyl] acetamide; N- (6-methoxy- (6-methoxy-1,3-benzothiazol-2-yl) -2- [4- (quinolin-4-yl) phenyl] acetamide; (6-methoxy-1,3-benzothiazol-2-yl) -2- (4-methylpyridin-4-yl) phenyl] acetamide; N- (6-methoxy-1-benzothiazol-2-yl) -2- [6- (quinolin-4-yl) pyridin-3-yl] acetamide; N- (6-methanesulfonyl-1,3-benzothiazol-2-yl) -2- [4- (pyridin-4-yl) phenyl] acetamide; n- (6-fluoro-3-benzothiazol-2-yl) -2- [4- (pyridin-4-yl) phenyl] acetamide; N - (1,3-benzothiazol-2-yl) -2- [4- (pyridin-4-yl) phenyl] acetamide. N- (6-methoxy-1,3-benzothiazol-2-yl) -2- [6- (pyridin-4-yl) pyridin-3-yl] acetamide; N- (6-methoxy-1,3-benzothiazol-2-yl) -2- [3-methyl-4- (2-methylpyridin-4-yl) phenyl] acetamide; N - (6-methoxy-1,3-benzothiazol-2-yl) -2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] acetamide; N- (6-methoxy-1,3-benzothiazol-2-yl) -2- [4- (2-methylpyrimidin-4-yl) phenyl] acetamide; N- [4- (pyridin-2-yl) -1,3-thiazol-2-yl] -2- [4- (pyridin-4-yl) phenyl] acetamide; N- [4- (pyridin-4-yl) -1,3-thiazol-2-yl] -2- [4- (pyridin-4-yl) phenyl] acetamide; n- (6-methoxy-1,3-b and 2-methyl-11- (4-methylpyridin-4-yl) phenyl] acetamide; 2- [6- (2-methylpyridin-4-yl) pyrimidin-3-yl] -N-14-phenyl-1,3-thiazol-2-yl) acetamide; N- (isoquinolin-3-yl) -2- [4- (pyridin-4-yl) phenyl] acetamide; N- (6-fluoro-1,3-benzothiazol-2-yl) -2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] acetamide; 2- [4- (pyridin-4-yl) phenyl] -N- (quinolin-2-yl) acetamide; N- (6-methoxy-1,3-benzothiazol-2-yl) -2- [5- (2-methylpyridin-4-yl) pyrimidin-2-yl] acetamide; N- (6-methoxy-1,3-benzotriazol-2-yl) -2- [5- (2-methylpyridin-4-yl) pyridin-2-yl] acetamide; 2- [3-methyl-4- (2-methylpyridin-4-yl) ethanol] phenyl] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (5-phenylpyridin-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (4-phenylpyridin-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [6- (trifluoromethoxy) -1,3-benzothiazol-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (5-phenyl-1,3-thiazol-2-yl) acetamide; N- (6-methoxy-1,3-benzothiazol-2-yl) -2- [4- (2-methoxypyridin-4-yl) phenyl] acetamide; 2- [4- (2-ethyl-pyridin-4-yl) phenyl] -N- (6-methoxy-1,3-benzothiazol-2-yl) acetamide; 2- [2-methyl-4- (2-methylpyridin-4-yl) phenyl] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; N- [4- (4-methoxyphenyl) -1,3-thiazol-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [4- (4-fluorophenyl) -1,3-thiazol-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [4- (3,4-difluorophenyl) -1,3-thiazol-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (6-phenylpyridin-3-yl) acetamide; N- (5-phenylpiperidin-2-yl) -2- [4- (pyridazin-4-yl) phenyl] acetamide; N- [5- (4-methylphenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [5- (3-methoxyphenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [5- (2-methoxyphenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [5- (4-methoxyphenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (5-phenylpyrazin-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridin-2-yl) pyridin-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; N- [5- (3-methylphenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl] -N- (5-phenylpyridin-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridin-3-yl) pyridin-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridin-4-yl) pyridin-2-yl] acetamide; 2- [2- (4- (2-methylpyridin-4-yl) phenyl] -N- (6-phenylpyridazin-3-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (4-phenylphenyl) acetamide; 2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- (5-phenylpyridin-2-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (2-phenylpyrimidin-5-yl) acetamide; 2- [4- (1H-imidazol-1-yl) phenyl] -N- (5-phenylpyridin-2-yl) acetamide; N- (6-phenylpyridin-3-yl) -2- [4- (pyridazin-4-yl) phenyl] acetamide; N- [5- (4-fluorophenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [5- (3-fluorophenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [5- (4-ethylpiperazin-1-yl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- {5 - [(2R, 65) -2,6-dimethyl-morpholin-4-yl] pyridin-2-yl} -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [4- (pyridin-3-yl) phenyl] acetamide; N- (6-fluoro-1,3-benzothiazol-2-yl) -2- [4- (pyridazin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- (5-phenylpyrimidin-2-yl) acetamide; N- (6-methoxy-1,3-benzothiazol-2-yl) -N-methyl-2- [4- (pyridin-4-yl) phenyl] acetamide; 2- [4- (pyridazin-4-yl) phenyl] -N- [4- (pyridin-3-yl) phenyl] acetamide; N- (6-phenylpyridazin-3-yl) -2- [4- (pyridazin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (1H-pyrazol-4-yl) pyridin-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyrazin-2-yl) pyridin-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridin-5-yl) pyridin-2-yl] acetamide; [4 ... (2-methylpyridin-4-yl) phenyl] -N- [4- (pyridazin-4-yl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -1- [5 (1,2,3,6-tetrahydropyridin-1-yl) pyridin-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridazin-3-yl) pyridin-2-yl] acetamide; 2- [5-methyl-6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- (6-phenylpyridin-3-yl) acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridazin-4-yl) pyridin-2-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [6- (morpholin-4-yl) pyridin-3-yl] acetamide; N- [5- (3-fluorophenyl) pyridin-2-yl] -2- [5-methyl-6- (pyridazin-4-yl) pyrazin-3-yl] acetamide; 2- [3-methyl-4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridin-2-yl) pyridin-2-yl] acetamide; 2- [3-methyl-4- (pyridazin-4-yl) phenyl] -N- [5- (pyridin-2-yl) pyridin-2-yl] acetamide; 2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- [5 "(pyridazin-3-yl) pyridin-2-yl] acetamide; N- [5- (pyridaz-3-yl) pyridin-2-yl] -2- [6- (pyridazin-4-yl) pyridin-3-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl] -N- [5- (pyrazin-2-yl) pyridin-2-yl] acetamide; N- [5- (3-fluorophenyl) pyridin-2-yl] -2- [5-methyl-6- (2-methylpyridin-4-yl) pyridin-3-yl] acetamide; N- [5- (3-fluorophenyl) pyridin-2-yl] -2- [4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [5- (pyridazin-4-yl) pyridin-2-yl] acetamide; N- [5- (3-fluorophenyl) pyridin-2-yl] -2 - [6 - ((2-methylpyridin-4-yl) pyridin-3-yl] acetamide; N- [6- (3-fluorophenyl) pyrimidin-3-yl] -2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] acetamide; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [6- (pyridazin-4-yl) pyridin-3-yl] acetamide; 2- [5-methyl-6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- [5- (pyrazin-2-yl) pyridin- acetamide; 2- [5-methyl-6- (pyridazin-4-yl) pyridin-3-yl] -N- (6-phenylpyridin-3-yl) acetamide; 2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- (6-phenylpyridin-3-yl) acetamide; N- (6-phenylpyridin-3-yl) -2- [6- (pyridazin-4-yl) pyridin-3-yl] acetamide; N- [6- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) pyridin-3-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; Methyl 4- (5- {2- (4- (2-methylpyridin-4-yl) phenyl] acetamido} pyridin-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylate; N- [ Yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [6- (1-methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl) pyridin-3-yl] Pyridine-3-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; 2- [5-methyl-6- (pyridazin-4 yl) pyridin-3-yl] -N- [5- (pyridin-2-yl) pyridin-2-yl] acetamide 2- [6- (pyridazin-4-yl) pyridin-3-yl] -N- 2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- (5-phenylpyrimidin-2-yl) ) acetamide: N- [5- (3-hydroxyethyl) pyrimidin-2-yl] -2- [6- (pyridazin-4-yl) pyridin-3-yl] acetamide; Ethyl 2- [4- (2-methylpyridin-4-yl) phenyl] acetyl] pyridin-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylate: 4- (5- {2- [4- - {2- [2- (2-methylpyridin-4-yl) phenyl] acetamido} pyridin-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylate; 4- (2-methylpyridin-4-yl) phenyl] acetamido} pyridine n-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylate; 2- [4- (2-methylpyridin-4-yl) phenyl] -N- [6- (1,2,3,6-tetrahydropyridin-4-yl) pyridin-3-yl] acetamide; N- [6- (3-fluorophenyl) pyridin-3-yl] -2- [5-methyl-6- (2-methylpyridin-4-yl) pyridin-3-yl] acetamide; N- [6- (3-fluorophenyl) pyridin-3-yl] -2- [5-methyl-6- (pyridazin-4-yl) pyridin-3-yl] acetamide; N- [6- (3-fluorophenyl) pyridin-3-yl] -2- [4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl] acetamide; N- [6- (3-fluorophenyl) pyridin-3-yl] -2- [4- (pyridazin-4-yl) -3- (trifluoromethyl) phenyl] acetamide; N- [6- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyridin-3-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [6- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) pyridin-3-yl] -2- [4- (2-methylpyridin-4-yl) phenyl] acetamide; N- [6- (3-fluorophenyl) pyridin-3-yl] -2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] acetamide; N- (6-phenylpyridazin-3-yl) -2- [6- (pyridazin-4-yl) pyridin-3-yl] acetamide; 2- [6- (2-methylpyridin-4-yl) pyridin-3-yl] -N- (6-phenylpyridazin-3-yl) acetamide; and N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (2,3'-bipyridin-6'-yl) -2- (4- (pyridazin-4-yl) -3- (trifluoromethyl) phenyl) acetamide; N- (5- (pyridazin-3-yl) pyridin-2-yl) -2- (4- (pyridazin-4-yl) phenyl) acetamide; N- (5- (3-fluorophenyl) pyridin-2-yl) -2- (6- (pyridazin-4-yl) pyridin-3-yl) acetamide; N- (6- (3-fluorophenyl) pyridin-3-yl) -2- (6- (pyridazin-4-yl) pyr]]] 3-yl) acetamide; N- (6- (1- (2-Amino-2-5-trans -hexyl) -1,2,3,6-tetrahydropyridin-4-yl) pyridin-3-yl) -2- (4- (2-methylpiperidin-4-yl) phenyl) acetamide; N- (6- (3-fluorophenyl) pyridin-3-yl) -2- (4- (pyridazin-4-yl) phenyl) acetamide; N- (5- (pyrazin-2-yl) pyridin-2-yl) -2- (4- (pyridazin-4-yl) -3- (trifluoromethyl) phenyl) acetamide; tert-butyl 4- (5- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-2-yl) piperazine- N- (2,3'-bipyridin-6'- N- (5- (3-fluorophenyl) pyridin-2-yl) -2- (4- (pyridazin-4-yl) yl) phenyl) acetamide; 2- (4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl) acetamidyl) pyridin-2-yl) -2- (4- (pyridazin-4-yl ) -3- (trifluoromethyl) -1H-imidazolyl) fluorophenyl) pyrimidin-5-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; N- {2,3'-bipyridin-6-yl) -2- (2 ', 3-dimethyl-2,4bipyridin-5-yl) acetamide; Tert-Butyl 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1-carboxylate; N- (2,2-bipyridin-6-yl) -2- (2'-methyl-2,4 '-bipyridin-5-yl) acetamide; (1-acetylpiperidin-4-yl) pyridin-3-yl) -2- (4- (2-methoxypyridin-4-yl) phenyl) acetamide; 2- (2-methyl-2,4 '-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; N- (5- (pyrazin-2-yl) pyridin-2-yl) -2- (6- (pyridazin-4-yl) pyridin-3-yl) acetamide; 2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; N- (o- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpridyn-4-yl) phenyl) acetamide; 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1-carboxylate; 2- (3-methyl-4- (pyridazin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; 2- (3-methyl-4- (pyridazin-4-yl) phenyl) -N- (5- (pyridazin-4-yl) pyridin-2-yl) acetamide; 2- (2 ', 3-dimethyl-2,4-bipyridin-5-yl) -N- (5- (pyridazin-4-yl) pyridin-2-yl) acetamide; 2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) -N- (6- (pyridazin-4-yl) pyridin-3-yl) acetamide; 2- (3-methyl-4- (pyridazin-4-yl) phenyl) -N- (o- (pyridazin-3-yl) pyridin-2-yl) acetamide; 4- (6- (2- (4- (2-Merylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperidine-1-carboxylate of 17β, 21403832Î ± -tert-butyl; 2- (3-methyl-4- (pyridazin-4-yl) phenyl) -N- (6- (pyridazin-4-yl) pyridin-3-yl) acetamide; 2- (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) -N- (5- (3-fluorophenyl) pyridin-2-yl) acetamide; 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5- (3-oxopiperazin-1-yl) pyridin-2-yl) acetamide; 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1-carboxamide; N- (5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; 2- (4- (4-methyl-1H-imidazol-1-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; 2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; 2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; 2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) -N- (5-pyridazin-4-yl) pyridin-2-yl) acetamide; N- (5- (4-acetyl-piperazin-1-yl) pyridin-2-yl) -2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) acetamide; N- (5 - ((3S, 5R) -4-acetyl-3,5-dimethylpiperazin-1-yl) pyridin-2-yl) -2 " (4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (4- (1-acetylpiperidin-4-yl) phenyl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (6- (4- (2-hydroxyethyl) piperazin-1-yl) pyridin-3-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (6- (3-fluorophenyl) pyridin-3-yl) -2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) acetamide; 2- (2 ', 3-dimethyl-2, 4'-bipyridin-5-yl) -N- (4- (pyrazin-2-yl) phenyl) acetamide; 2- (2 ', 3-dimethyl-2,4-bipyridin-5-yl) -N- (4- (pyridazin-3-yl) phenyl) acetamide; 2- (2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) acetamido) -5- (pyrazin-2-yl) pyridine 1-oxide; 1'-2 ', 3-dimethyl-5- (2-oxo-2- (5- (pyrazin-2-yl) pyridin-2-ylamino) ethyl) -2,4-bipyridine oxide; 2- (2 ', 3-dimethyl-2,41-bipyridin-5-yl) -N- (6- (pyrazin-2-yl) pyridin-3-yl) acetamide; N- (5- (4-isobutyl-1-piperazin-1-yl) pyrimid-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetylamino) (5-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methyl-4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (6- (4-Acetylpiperazin-1-yl) pyrimidin-3-yl) -2- (21,3-dimethyl-2,4 '-bipyridin-5-yl) -acetyl] acetamide; (R) -N- (6- (4-acetyl-3-methyl-piperidinyl) pyridin-3-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; (S) -N- (6- (4-acetyl-3-methylpiperazin-1-yl) pyridin-3-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; (S) -N- (6- (4-acetyl-3-methylpiperazin-1-yl) pyridin-3-yl) -2- (2,3-dimethyl-2,4'-bipyridin-5-yl) acetamide; (R) -N- (6- (4-acetyl-3-methylpiperazin-1-yl) pyridin-3-yl) -2- (2 ', 3-dimethyl-2,41-bipyridin-5-yl ) acetamide; N- (5 - ((3S, 5R) -4-acetyl-3,5-dimethylpiperazin-1-yl) pyridin-2-yl) -2- (2 ', 3-dimethyl-2,4'-bipyridin- 5-yl) acetamide; methyl 4- (6- (2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) acetamido) pyridin-3-yl) piperazine-1-carboxylate; Methyl 4- (6- (2- (3-methyl-4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1-carboxylate; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-fluoro-4- (2-methylpiperidin-4-yl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl-2, 4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-chloro-4- (2-methylpyridin-4-yl) phenyl) acetamide; Ethyl 4- (6- (2- (2 ', 3-dimethyl-2,41-bipyridin-5-yl) acetamido) pyridin-3-yl) piperazine-1-carboxylate; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl) acetamide; 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) -N- (6-phenylpyridin-3-yl) acetamide; 2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) -N- (5- (4-propionylpiperazin-1-yl) pyridin-2-yl) acetamide; N- (5- (4- (cyanomethyl) piperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (5- (4-cyanopiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-chloropyridin-4-yl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyrimidin-2-yl) -2- (4- (2-fluorophenyl) -4H-phenyl) acetamide; 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) -N- (6- (pyrazin-2- (3-cyano-4- (2-yl) pyridin-3-yl) acetamide ; 19β, 40β, 32β-methylpyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methoxy-4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-chloro-2'-methyl-2,4'-bipyridin-5-yl) acetamide; (S) -N- (5- (4-acetyl-3 - [(2-methylethyl) methylpyridin-4-yl) pyridin-2-yl) cyano-4- (2-yl) phenyl) acetamide; (R) -N- (5- (4-acetyl-3-erazin-1-yl) pyridin-2-yl) -2- (2 ', 3-dimethyl- acetamide; Isopropyl 4- (6- (2- (2 ', 3-dimethyl-2,4-dibin-5-yl) acetamido) pyridin-3-yl) piperazine-1-Ipiperazin-methoxy bip-carboxylate; N- (5- (4-ethyl) pyridin-2-yl) -2- (3-cyano-2'-methyl-2,4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl-3- (trifluoromethyl) -2,4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-fluoro-2'-methyl-2 ', 4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2-fluoro-5-methyl-4- (2-methylpyridin-4-yl) phenyl) acetamide; N- (5- (4-Acetylpiperazin-1-11) p-androst-2-yl) -2- (4- (2-methylpiperidin-4-yl) -3- (trifluoromethyl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2 ', 3-difluoro-2,4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyrimidin-4-yl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (5-fluoropyrimidin-4-yl) phenyl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl-3- (methylsulfonyl) -2,4'-bipyridin-5-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (6-methylpyrimidin-4-yl) phenyl) acetamide; 2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; 2- (4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2- (dlfluoroethyl) pyridin-4-yl) phenyl ) actamide; N- (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) -2- (4- (2- (trifluoromethyl) pyridin-4-yl) phenyl) acetamide; 2- (difluorophenyl) pyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin- 2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (5-fluoropyrimidin-4-yl) -3-methylphenyl) acetamide; 2- (2 R, 3-difluoro-2,4-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) acetamide; 2 - (2'-fluoro-2,4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-2,4'-bipyridin-5-yl) acetamide; 2 - (2 1,3-difluoro-2,41-bipyridin-5-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetamide; 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; 2- (4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; and 2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide; or physiologically acceptable salts thereof.

In another embodiment, compounds selected from the group consisting of:

21 ΕΡ2403832Β1

In another preferred embodiment are compounds having Formula (10) or (11):

A2 (11) thereof, (10) or a physiologically salt wherein: ring E is an optionally substituted aryl or heteroaryl; A1 and Az are independently a C1-6 heterocycle, quinolinyl, or a heteroaryl selected from the group:

Wherein each heterocycle of A1 and Az may be optionally substituted with -LC (O) R1U; wherein the nitrogen may be optionally oxidized (see, for example, compound 156 of table 1). B is benzothiazolyl, quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 groups R °;

XJ X " X 'are independently CR' Y is phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; Z is aryl, Cl-5 heterocycle, or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; each Y and Z are optionally substituted with 1-3 R6 groups; R 1 and R 2 are independently H or C 1-6 alkyl;

R 2 and R 3 are independently H, C 1-6 alkyl or halo; R4 is halo, cyano, C1 -C8 -alkoxy, or a C1- 5 -alkyl optionally substituted with halo, alkoxy or amino; R6 is hydrogen, halo,: oxy, -S (O) 2 R10, -C (O) OR10, -C (O) R10, -C (O) NR8 R9, C1-6 alkyl, C2-8 alkenyl or C1-

alkynyl, each of which may be unsubstituted or substituted with halo, amino, hydroxy, cyano; halo, CN, -LW, NI8R9, -I, -C (O) R1G, -L-LC (O) NR8R9, o-LS (O) or 2R or -LS (O) R 7 is H, halo, C 1-6 alkoxy, -S (O) 2 R 10, cyano, C 1-8 alkoxy, C 1-6 alkyl, optionally substituted with halo, amino, hydroxy, alkoxy or amino; Q Q NRh R ', (O) R 1 -L-C (O) NR 8 R 9, OR 10; -L-S (O) 2 R 1 U or -L-S (O) 2 NR 8 R 9;

Ra and R9 are independently H, -L-W, or C1-6 alkyl, C2-6 alkenyl or C2-8 alkynyl, each of which may be optionally substituted with halo, amino, hydroxy, alkoxy or cyano; or R8 and R9 together with the atoms to which they are attached may form a ring; R10 is H, -L-W, or C1-6 alkyl, C2-8 alkenyl or C2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxy, alkoxy or cyano; L is a bond or (CR 2) 1-4 wherein R 1 is H or C 1-6 alkyl; W is C3-7 Cycloalkyl, C1-6 heterocycle, aryl or heteroaryl; m and 4; n is 0-3; is 0-2; and the solvates, hydrate n-oxide derivative or prodrugs thereof.

In another embodiment, the compounds of Formula (I) are those selected from the group consisting of: N- (6-methoxybenzo [d] thiazol-2-yl) -2- (3- (pyridin-4-yl) phenyl ) acetamide; N- (6-phenylpyridin-3-yl) -2- (3- (pyridin-4-yl) phenyl) acetamide; 2- (3- (2-methylpyridin-4-yl) phenyl) -N- (6-phenylpyridin-3-yl) acetamide; N- (6-phenylpyridin-3-yl) - (pyridazin-4-yl) phenyl) acetamide; 2- (3- (2-methoxypyridin-4-yl) phenyl) -N- (6-phenylpyridin-3-yl) acetamide; N- (5- (4-acetyl-piperazin-1-yl) pyridin-2-yl) -2- (3- (2-methylpyridin-4-yl) phenyl) acetamide; 2- (3- (2-methylpyridin-4-yl) phenyl) -N- (4- (pyridazin-3-yl) phenyl) acetamide; 2- (3- (2-methylpyridin-4-yl) -phenyl) -phenyl) -N- (4- (pyrazin-2-yl) phenyl) acetamide; 2- (3- (2-methyl-pyridin-4-yl) phenyl) -N- (6- (pyrazin-2-yl) pyridin-3-yl) acetamide; 2- (2'-methyl-2, 4 * -bipyridin-6-yl) -N- (6-phenylpyridin-3-yl) acetamide; 2- (2'-methyl-2,4 '-bipyridin-4-yl) -N- (6-phenylpyridin-3-yl) acetamide; 2- (4-cyano-3- (2-methylpyridin-4-yl) phenyl) -N- (6-phenylpyridin-3-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-cyano-3- (2-methylpyridin-4-yl) phenyl) acetamide; 2- (2'-methyl-2,4'-bipyridin-4-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide; N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl-2,4 '-bipyridin-4-yl) acetamide; and N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2-cyano-2'-methyl-3,4,5-bipyridin-5-yl) acetamide, or a salt pharmaceutically acceptable salts thereof.

Also disclosed herein are pharmaceutical compositions comprising a compound having Formula (1), (2), (3), (4), (5) or (6), and a physiologically acceptable carrier.

Also disclosed herein are methods for inhibiting Wnt signaling in a cell comprising contacting the cell with an effective amount of a compound having Formula (1), (2), (3), (4), (5) or (6), or a pharmaceutical composition thereof.

Also disclosed herein are methods for inhibiting a porcupine gene in a cell comprising contacting the cell with an effective amount of a compound having Formula (1), (2), (3), (4 ), (5) or (6), or a pharmaceutical composition thereof.

Also disclosed herein are methods for preventing a Wnt-mediated disorder comprising administering to the mammal a therapeutically effective amount of a compound having Formula (1), (2), (3), (4), (5) or (6), or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent. Also described herein is the use of a compound having the Formula (1), (2), (3), (4), (5) or (6), and optionally in combination with a second therapeutic agent, in the manufacture of a medicament for the treatment of a Wnt-mediated disorder.

The compounds described herein may be administered, for example, to a mammal suffering from a Wnt-mediated disorder selected from keloids, fibrosis such as skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis and liver fibrosis; proteinuria, kidney graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema (CME) such as EMC associated with uveitis; retinopathy such as diabetic retinopathy, or retinopathy of prematurity; macular degeneration and a cell proliferation disorder associated with aberrant Wnt signaling activity.

In particular examples, the compounds described herein may be used alone or in combination with a chemotherapeutic agent to treat a non-cell carcinoma of a cell proliferation disorder, including, but not limited to, colorectal cancer, breast cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, pancreatic cancer, leukemia, lymphoma, neuroblastoma, retinoblastoma, sarcoma, osteosarcoma, condossarcoma, Ewing's sarcoma, rhabdomyosarcoma, tumor-brain, tumor of the head and neck. Wilm, basal cell carcinoma, melanoma, head and neck cancer, cervical cancer and prostate cancer. EP24G3832B1) and " Alkyl " refers to a moiety and as a structural element of other groups, for example, halo-substituted alkyl and alkoxy, and may be straight chain or branched. An optionally substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (for example, CF3), or may have one or more carbons which is substituted or substituted with a hetero atom, such as NR10, or S -OCH 2 CH 2 -, alkylthio, thioalkoxy, alkylamines, etc.).

A " carbocyclic ring " as used herein refers to a monocyclic, bicyclic, fused or bridged-bonded or partially unsaturated polycyclic ring containing carbon atoms, which may optionally be substituted, for example, with = 0. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

A " heterocyclic ring " as used herein is as defined for a carbocyclic ring above, wherein one or more ring carbons are a heteroatom. For example, a heterocyclic ring may contain N, O, S, -N = C (O) (see, for example, compound 141, table 1), -S-, -S (O), -S O) 2 -, or -NR- wherein R may be hydroxy-N-azahydrogen, C1-4 alkyl or a protecting group. Examples of heterocyclic rings include, but are not limited to morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1,4-piro [4,5] dec-8-yl, and the like.

m H atom

As used herein, ε2403832Β1 in any substituent groups (e.g., CH2) embraces all suitable isotopic variations, for example, H, 2H and JH.

A " Wnt protein " is a ligand of the signaling pathway of the non-binding component Wnt. to a mill rizzled receiver to activate the Wnt signaling. Examples and Wnt include at least 19 d < (RefSeq: NM_u 04185), NM_033131), NM_003391), Wnt-3 (ReSeq Wnt-1 (RefSeq NM_003392), Wnt-5B ( (RefSeq: NM_005430), Wnt-2 Wnt-2B (Wnt-13) (RefSeq .: NM_030753), Wnt-7A (RefSeq. NM_058238), Wnt-8A (RefSeq.

Wnt-3A (RefSeq .: NM_030761), Wnt-5A (RefSeq .: NM_ 032642), Wnt-6 (RefSeq .: NM__u0462o), Wnt-7B (RefSeq .: NM_058244), Wnt-8B (RefSeq .: NM_003393), Wnt-9A (Wnt-14) (RefSeq .: NM_003395), Wnt-9B (Wnt-15) (RefSeq .: NM_003396), Wnt-IOA (RefSeq .: NM_025216), Wnt-IOB (RefSeq .: NM_003394), Wnt-11 (RefSeq .: NM_004626), Wnt-16 (RefSeq .: NM_016087)). While each member has varying degrees of sequence identity, each contains 23-24 conserved cysteine residues that show highly conserved spacing. McMahon, A P er al, Trends Genet. 8: 236-242 (1992); Miller JR, Genome Biol. 3 (1): 3001.1-3001,15 (2002). For the active iriative purposes of the Frizzled am ECD or the invention, a Wn protein is itself a protein which binds to the CRD component of such an E < 3D Frz • A "Wnt-mediated disorder is a disorder, condition, or disease state characterized by aberrant wnt signaling. In a specific aspect, aberrant Wnt signaling is a level of signal signaling in a cell or tissue suspected to be diseased that exceeds the level of Wnt signaling in a similar non-diseased cell or tissue. In a specific aspect, a disorder mediated by 28 ΕΡ2403832Β1

Wnt includes cancer. The term " cancer " refers to the physiological condition in mammals which is typically characterized by unregulated cell growth / proliferation. Examples of cancer include, but are not limited to: carcinoma, lymphoma, blastoma, and leukemia. More particular examples of cancers include, but are not limited to: chronic lymphocytic leukemia (L1C), lung, including non-small cell (NSCLC), breast, ovary, cervix, endometrial, prostate, colorectal, carcinoid intestinal, bladder, gastric, pancreatic, hepatic (hepatocellular), hepatoblastoma, esophageal, pulmonary adenocarcinoma, mesothelioma, synovial sarcoma, osteosarcoma, squamous cell carcinoma of the head and neck, juvenile nasopharyngeal angiofibromas, liposarcoma, thyroid, melanoma, basal cell carcinoma (BCG), medulloblastoma and desmoid. " Treat " or " treatment " or " relief " refers to both therapeutic and prophylactic treatment or preventive measures, wherein the object is to prevent or decelerate (decrease) the target pathological disease or condition or disturia. Those in need of treatment include those already with the disorder as well as those prone to having the disorder or those in whom the disorder is to be prevented (prophylaxis). When the Wnt-mediated disorder is cancer, an individual or mammal is " treated " succeeds or exhibits a reduced tumor burden if upon receipt of a therapeutic amount of a Wnt antagonist according to the methods of the present invention the patient shows observable and / or measurable reduction in or absence of one or more of the following : reduction in the number of cancer cells or absence of the cancer cells; reduction in tumor size; inhibiting the infiltration of cancer cells into peripheral organs including spreading 29 ΕΡ2403832Β1 cancer in bone and tissue; inhibition of tumor metastasis; inhibition to a certain extent of tumor growth; and / or relieving to some extent, one or more of the symptoms associated with the specific cancer; reduced morbidity and mortality, and improved quality of life problems. To the extent that the Wnt antagonist can prevent the growth and / or destruction of existing cancer cells, it may be cytostatic and / or cytotoxic. The reduction of these signs or symptoms can also be felt by the patient. "Mammal" means any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pets, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. In certain embodiments, the mammal is a human. Administration " in combination with " one or more additional therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order. The term " pharmaceutical combination " as used herein refers to a product obtained from the mixture or combination of active ingredients, and includes both the fixed and non-fixed combinations of the active ingredients. The term "active ingredients" (1) and a coagent, simultaneously in " fixed combination " means that, for example, a compound of Formula are both administered to a patient in a single entity form or dosage. The term " combination not fixed " means that the active ingredients, for example a compound of Formula (1) and a coagent, are both administered to a patient as separate entities simultaneously, concurrently or sequentially with no specific time limit, wherein such administration provides therapeutically levels of 30 ΕΡ2403832Β1 ΕΡ2403832Β1 active in the patient's body. 0 to cocktail therapy, for three or more. most effective ingredients of the last ingredients also applies example, the active administration. 'Porsaaores " as used herein encompass pharmaceutically acceptable carriers, excipients, or stabilizers that are non-toxic to the cell or mammal being exposed thereto at the dosages and concentrations used. Often the carrier i. i s i o .1 ogi cament e ace r t. a.ve 1 buffered. Examples of is a pharmaceutically acceptable acidophilic pH aqueous solution include buffers such as other organic acids; ascorbic acid; molecular weight antioxidants including low acid (less than about 10 residues) polypeptide; proteins, such as serum albumin, gexatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt forming counterions such as sodium; and / or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

An " effective amount " of a compound (e.g., a Wnt antagonist) is an amount sufficient to carry out a specifically indicated purpose. An " effective amount " can be determined empirically and routinely, for the stated purpose. The term " therapeutically effective amount " refers to an amount of a Wnt antagonist effective for " treating " a Wnt-mediated disorder in a mammalian individual or ΕΡ2403832Β1. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce tumor size; inhibit (ie decelerate to some extent or stop) the infiltration of cancer cells into peripheral organs; inhibit tumor metastasis; inhibit, to some extent, tumor growth; and / or alleviating to some extent one or more of the symptoms associated with the cancer. See the definition in this " treatment " document. To the extent that the drug can prevent the growth and / or destruction of existing cancer cells, it may be cytostatic and / or cytotoxic.

A " chemotherapeutic agent " is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethemines and methylamelamines including altretamine, trimethylaminopyridine, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bulatacin and bulatacinone); delta-9-tetrahydronaphthalene (dronabinol, MARINOL®); beta-lapacone; lapacol; colchicines; betulinic acid; a camptotheme (including synthetic topotecan analogue (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); briost; ealistatin; CC-1065 (including

Synthetic analogs adozelesine, carzelesine and bizelesin); podo filotoxin; podophyllinic acid; teniposide; cryptoficins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleuterobina; pancratistatin; a sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquin, fenesterin, prednisone, family fungus, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyna antibiotics (for example, calicheamicin, especially calicheamicin gamma11 and calicheamicin omegall (see, for example, Agnew, Caem Intl, Ed. Engl., 33: 183-186 (1994)); A, an indole morpholinyl, 2-pyrrolidinyl, tert-butyl, naphthyl, naphthyl, cyano, inorganic, streptozoto, zorubicin; air. thluorouracil (b-E u); such as denitrite, purine urine analogues, thiamine, and the like, such as cytarabine, esperamicam; has as chromosome of neocarzinostatin and chromophores of related enediyne chromoprotein antibiotics), aclacinomisinas, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, cimetidine, cimetidine, cimetidine, dactinomycin, daunorubicin, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone; analogues of folic acid such as methotrexate, pteropterin, trimetrexate, such as fludarabine, 6-mercaptothioguanine, analogs of pyrimidine i azacytidine, 6-azauridine, carodideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid such as frolic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene: edatraxate; defofamina; demecolcin; ΕΡ2403832Β1 diaziquone; elfomitin; ϊ C θ X, 3 d elliptin; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oregon); reasonable; rhizoxin; sizofuran; spirogermánio; tenuazonic acid; triaziquone; 2,2 ', 2 "-trichlorotriethylamine; trichhotecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine (ELDISINE®, FILDESIN®); sazina; mannomust ina; my t obronit o1; mitolactol; pipobroman; gacitosine; arabinoside (" Ara-C ");thiotepa; Taxoides, for example, Paclitaxel TAXOL (Bristol-Myers Squibb Oncology, Princeton, NJ), free-flowing enzyme nanoparticle formulation of Cremofor ABRAXANE ™ from Paclitaxel (American Pharmaceutical Partners, Schaumberg, 111) and TAXOTERE® doxetaxel (Rhône -Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin; ammopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine (XELODA®); pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; as well as combinations of two or more of the above such as CHOP, a. abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for 34 ΕΡ2403832Β1 an oxaliplatin treatment regimen (ELOXATIN ™) combined with 5-FU and leucovovin.

In addition, a " chemotherapeutic agent " can include anti-hormonal agents that appear to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and are often in the systemic or whole body treatment regimen. They can be hormones by themselves. Examples include antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), EVISTA® raloxifene, droioxyphene, 4-hydroxytamoxifen, trioxifene, queoxifene, LY117018, onapristone, and toremifene FARESTON ®; anti-progesterones; estrogen receptor negative regulators (ERDs); agents which function to suppress or turn off the ovaries, for example, luteinizing hormone releasing hormone (LHRH) agonists such as LUPRON® and ELIGARD® leuprolide acetate, goserelin acetate, buserelin acetate and tripterelin; other anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors which inhibit the aromatase enzyme, which regulates the production of estrogen in the adrenal glands, such as, for example, 4 (5) -imidazole, aminoglutethimide, megestrol acetate MEGASE®, AROMASIN® exemestane, formestanie, fadrozole, vorozol RIVISOR®, letrozole FEMARA®, and anastrozole ARIMIDAX®. In addition, such a definition of chemotherapeutic agents includes bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), DIDROCAL® eticlronate, NE-58095, zoledronic acid / zoledronate ZOMETA®, alendronate FOSAMAX®, pamidronate ARE D IA.®, SKELID® tiludronate, or risedronate AC TONEL®; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analogue); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R ); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitor LURT 0 TE CAN®; ABARELIX® rmRH; lapatinib ditosylate (a small molecule inhibitor of ErbB-2 double-stranded tyrosine and EGFR also known as GW572016); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

The present invention relates to compositions and methods for modulating the Wnt signaling pathway. and document a compound

Also described in the preset having Formula (1) or (2):

Z

0)

xk X2

or a physiologically acceptable salt thereof, wherein: ring E is an optionally substituted aryl or heteroaryl; A1 and A " are independently a C 1-6 heterocycle, quinolinyl, or a heteroaryl selected from the group:

36 ΕΡ2403832Β1

of A1 and A2 optionally substituted with -LC (O) R1U; benzothiazolyl, quinolinyl or isoquinolinyl, each of which is optionally substituted with 1-3 R 5 groups; wherein any heterocycle

may be B1, X1, X2, X1 and X4 are independently CR7 or N; Y is phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; Z is aryl, C 1-5 heterocycle, or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; each Y and Z are optionally substituted with 1-3 groups R °; R 1 and R b are independently H or C 1-6 alkyl; R " and R 3 are independently H, C 1-6 alkyl or halo; R4 is halo, cyano, C1-6 alkoxy, or a C1-6 alkyl optionally substituted with halo, alkoxy or amino; R3 is hydrogen, halo. C 1 -C 6 -alkoxy, -S (O) 2 K °, -C (O) OR 10, -C (O) NR 8 R 9, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted amino, hydroxyl, alkoxy or cyano; halo, CN, -L-W, NRSR9, -L-, -O-, -C (O) OR10, -L-C (O) NR8R9, OR10; -L-S (O) 2 R 10 or -L-s (O) 2nr8: O 'R' and H, C1-6 alkyl amino, hydroxy, -L-C (O) NR8 R9, OR10; halo, C1-6 alkoxy, -L-S (O) 2 R11 optionally substituted with halo, alkoxy or cyano; NR 8 R 9, -L-C (O) R 11, -L-S (O) 2 R 10, or -L-S (O) 2 NR 8 R 9; R8 and R9 are independently H, -L-W, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxy, ΕΡ2403832Β1 ΕΡ2403832Β1 alkoxy or cyano; or RJ and FR along with the ones joined together may form a ring; u is H, 1, W, or C 1-5 alkanoyl, C 2-8 alkynyl, or each of which may be optionally substituted with halo, amino, hydroxy, alkoxy or cyano; L is a bond or (CR 2) 1-4 wherein R 1 is H or C 1-6 alkyl; W is C--C-cycloalkyl, heteroaryl; m is 0-4; n is C15 heterocycle, j-3; and " P is 0-2 or pyridinyl, may be phenyl, thiazolyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted with 1-2 groups R6 and R5 is as defined herein. Z may be phenyl, pyridinyl, pyridazine, pyrimidine, pyrazine, piperazinyl, piperidinyl, morpholinyl, pyrazole or 1,2,3,6-tetrahydropyridine, each of which is optionally substituted with 1 R6 and R6 groups are as defined herein. A ± and A2 may independently be morpholinyl, piperazinyl, quinolinyl,

38 ΕΡ2403832Β1

wherein any heterocycle of Ά 1 and Az may be optionally substituted with -C (O) CH 3; R4, m, n and p are as defined in the disclosure of the invention.

Also described herein is a compound of Formula (3):

R 3, X 1, X 2, X 3, X 4, A 2 and wherein R 2 is as defined herein. They are like, pray.

Also described herein is a compound of Formula (4):

(4) wherein R ', Pc, defined in the disclosure of the invention, and Z are as they were

Ring E may be phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with R ". R 'may be H, halo, cyano, C1-6 alkoxy, -S (O) 2 Rz, h or a 39 ΕΡ2403832Β1

C1-6 alkyl optionally halogenated.

It is also described

a compound wherein A1 is piperazinyl substituted with -C (O) CH;

7T

, S (O) C

Hi

V6 is one of X1, X6, X7 and X8 is N and the others are CR11; Z is a 6-membered heterocycle or a 6-membered heteroaryl, each containing 1-2 heteroatoms of nitrogen and each of which is optionally substituted with 1-2 groups R 6; R1, R " and Rb are H or C1-6 alkyl; R4 and R6 are independently hydrogen, cyano, C1-6 alkoxy, S (O) 2 R10, -C (O) NR9 R9, -LC (O) R10, -L-C (O) OR10, C1-6 alkyl optionally substituted with halo, C2- and alkenyl or C2- and alkynyl;

R10 is C1-6 alkyl or -L-W; L is a bond or (CR 2) 14 wherein R 1 is H or C 1-6 alkyl; W is C3-7 cycloalkyl; R 1 and R 11 are independently H, halo, cyano, C 1-6 alkoxy, - S (O) 2 R 10, or an optionally halogenated 2-6 alkyl; and m, n and p are independently 0-2. A1 may be piperazinyl substituted with -C (O) CH3,

or selected from:

41 ΕΡ2403832Β1

Also described herein is a compound of Formula (6): ΕΡ2403832Β1

of N and or? m of Xo, Xc, X; and X8 is N and the others are CH; X 9 is selected from N and CH; Z is selected from phenyl, pyrazinyl, pyridinyl and piperazinyl; wherein each phenyl, pyrazinyl, pyridinyl or piperazinyl of Z is optionally substituted with one R6 group; R1, R2 and R3 are hydrogen; m is 1 - R 4 is selected from hydrogen and methyl; R ° is and / or C = O; wherein R1 is methyl; and halo and R 'is selected from hydrogen, methyl, and trifluoromethyl. R 3 are H; and R1 and R2 are hydrogen,

In some compounds, R 1, R 2 and independently are halo, methyl and -C (O) CH 3. carb (R), in each of the asymmetric rings (S) or (R, S). The above formulas, any Î ± 2403832Β1 may be present in the configuration of compounds as mixtures of isomers or as pure isomers, for example as pure enantiomers or diastereomers. Possible tautomers of the inventive compounds are also described herein.

Also described herein are all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one wherein at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention are pharmaceutically acceptable salts thereof, but not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as 2H, 3H, 15, 18, 36, 31 and 13'I. The isotopic variations of the compounds of the invention and the pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3-1 or 14C is incorporated, are useful in drug and / or substrate tissue distribution studies.

In particular examples, the isotopes ZH, 3H and 14C can be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as ZH may provide certain therapeutic advantages resulting from increased metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof may generally be prepared by standard procedures using appropriate isotopic variations of suitable reagents. Isotopic variations of the compounds have the potential to change a metabolic fate of the compound and / or create minor changes in physical properties such as hydrophobic acid, and the like. Isotopic variation has the potential to increase efficacy and safety, increase oxodisability and half - life, alter protein binding, change a. bioavailability, increase the metaool.it proportion of the active and / or decrease the formation of metabolite: reactive or toxic.

Also disclosed herein is a method of inhibiting Wnt signaling in a cell comprising contacting the cell with an effective amount of a Wnt dutagonisLâ "¢. The cell may be contained within a manuiero, and the amount administered may be a therapeutically effective amount. Inhibition of Wnt neutralization may further result in inhibition of the presence of the cell. The cell may be a cancer cell. Inhibition of cell proliferation is measured by methods known to the skilled person. For example, a convenient assay for measuring cell proliferation is the CellTiter-Glo ™ Luminescent Cell Viability Assay, which is commercially available from Promega (Madison, Wis.). This assay determines the number of viable cells in culture based on the ATP quantification present, which is an indication Crouch et al. No. 6,602,677. or 384 wells of metabolically active cells. (1993) J. Immunol. Met. 160: 81-88, IJS Patent The assay can be conducted in 96 format, making it amenable to automated high throughput screening (HTS). See Cree et al (1995) AntiCancer Drugs 6: 398-404. the assay procedure involves adding a single reagent (CellTiter-Glo® Reagent) directly to cultured cells. This results in cell lysis and generation of luminescence signal produced in the absence of luminescence is present, which is due to a luciferase reaction. 0 s proportional to the amount of ATP directly proportional to the number prevailing in culture. The data may be a minometer or CCD i-forming device. The luminescence result is recorded by the camera expression expressed as relative light units (RLU). Inhibition of cell proliferation can also be measured using colony forming assays known in the art.

Also disclosed herein are methods of treating a Wnt-mediated disorder in a mammal suffering therefrom, which comprises administering to the mammal a therapeutically effective amount of an antagonist of

Wnt. The disorder may be a disorder of cell proliferation associated with aberrant, e.g., increased, expression of Wnt signaling activity. The disorder may result from increased expression of a Wnt protein. The cell proliferation disorder may be cancer, such as, for example, colon cancer, colorectal cancer, breast cancer, cancer associated with various HSC related disorders such as leukemias and various other blood related cancers, and cancer related to disturbs. such as gliomas, astrocytomas, meningiomas, Schwannomas, pituitary tumors, primitive neuroectodermal tumors (TNEP), medulloblastomas, craniopharyngioma, pineal region tumors, and skin cancers including basal cell carcinoma and carcinoma of the brain. squamous cell. Treatment of the cell proliferation disorder by administration of a Wnt antagonist results in an observable and / or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or the absence of cancer cells; reduction in tumor size; inhibiting the infiltration of cancer cells into peripheral organs including the spreading of cancer in " being "bone; inhibition. tumor assay; even at the very least, of the tumor growth; and / or the proviso of one or more of the sequences c < with the specific cancer being morbidity and mortality at the time of the problem of virile 3. As the Wnt antagonist is able to predict the e / or destroy cell phone rings' " i " There are, for example, attic and / or cyano +. The red uction of these S 1] nts but may also be felt by the patient, relief

The above parameters for evaluating successful treatment and improvement in disease are readily measurable through routine procedures familiar to a physician.

For the therapy 0 0 " Ci 1 "τ 'the cam vr', ci C - r '-' '' '' '' '' for example, from time to time evaluation. (TP D) and / or of the recovery of the reaction (TR). The metastasis can be determined by mc10 of the tests of the sample and by the presence of samples and tests for the level of calcium and other enzymes to determine the spread. CT scans may also be done to search the pelvic spine and pelvic nodes in the area. Chest X-rays and the measurement of liver enzyme levels by known methods are used to look for metastasis in the lungs and liver, respectively. Other fp, 0 rotom t for moni ul t rre transrectal onog r e ra tio n (TRNB) * In a f o rm Ά ζΊ m i n s tration of. The anti-agonist (eg, reduces the size of the needle), and the needle biopsy. specific realization, sm

LyC '13 f 3. 46 ΕΡ240383261

Pharmacology and Utility

Also described herein are compositions and methods for modulating the Wnt signaling pathway. Also described herein are compositions and methods that inhibit Wnt signal transduction activity by modulating pathway activation. of Wnt, thereby treating, diagnosing, preventing, and / or ameliorating relationship disorders with Wnt signaling. The present paradigm for developing therapies for disorders related to Wnt signaling is based on the targeting of β-cat or components of the Wnt pathway downstream of β-cat. Recent studies, however, suggest that inhibition of the extracellular receptor-ligand interaction component is effective in reducing tumorigenicity, even though the event initiating Wnt signaling may have occurred downstream. In addition, transfection of frizzled receptor inoperative (Frz7 ectodo minio) in 1i. of cell. (SK-CO-1) restored a normal β-catenin phenotype. This cellulic line has active Wnt signaling

Such tumor cells arising due to a homozygous APC mutation also did not demonstrate the formation of > ifferentiation 2005; In vivo, Vincan et al., 73: 142-153. This demonstrates that inhibition of Wnt signaling at the extracellular level can negatively regulate Wnt signaling resulting from the activation of a downstream intracellular Wnt signaling pathway component. This further suggests that inhibitors of the Wnt signaling pathway may be used in the treatment of any Wnt-mediated disorder, regardless of the particular way in which Wnt signaling has been activated. 47 ΕΡ2403832Β1

Disorders Associated with Wnt Signaling Activity Dysregulation of the Wnt signaling pathway can be caused by somatic mutations in genes encoding various components of the Wnt signaling pathway. For example, aberrant Wnt signaling activity has been associated with overexpression of Wnt ligand in non-small cell lung cancer (NSCLC) [You et al., Oncogene 2004; 23: 6170-6174], chronic lymphocytic leukemia (CLL) [Lu et al. , Proc. Natl. Acaci. Know. USA 2004; 101: 3118-3123], gastric cancer [Kim et al., Exp. Oncol. 2003; 25: 211-215; Saitoh, 19], Int. J. Mol. Med. 2002; 9: 515-229, squamous cell carcinoma of the head and neck (HNSCC) [Rhee et al., Oncogene 2002; 21: 6598-6605], colorectal cancer [Holcombe et al., J. Ciin. Pathol-Mol. Pathol. 2002; 55 Ϊ20- of: io cancer Λ i

Endocrinology 2002; 143: 2741-2749], basal cell carcinoma (BCC) [Lo Muzio et al., Anticancer Res. 2002; 22: 565-576] and breast cancer. In addition, the reduction of various Wnt ligand regulatory molecules such as sFRP and WIF-1 has been associated with breast cancer [Klopocki et al., Int. J. Oncol. 2004; 25: 641-649; Ugolini et al., Oncogene J. Pathol 2003; 201: 2001; 20: 5810-5817; Wissmann et al.,

Lab Invest. mesothelioma et supra 204-212], bladder cancer [Stoehr 2004; 84: 465-478; Wissmann et al.

[Lee et al., Oncogene 2004; 23: 6672-6676], colorectal cancer [Suzuki et al., Nature Genet. 2004; 36: 417-422;

Kim et al., Mol. Cancer Ther. 2002; 1: 1355-1359; Caldwell et al., Cancer Res. 2004; 64: 883-888], prostate care [Wissman et al., Supra], NSCLC [Mazieres et al., Cancer Res. 2004; 64: 4717-4720], and lung cancer [Wissman et al., Supra]. Aberrant Wnt signaling resulting from overexpression of various components of the Frz-48 ΕΡ2403832Β1 receptor complex was also associated with certain cancers. For example, sore-expression of LRP5 was associated with osteosarcoma [noang et al., Inu. j. Cancer 2004; 109: 106-111], whereas Frore sorepression was associated with cancers such as cancer and prostate [Wissmann et al., Supra], HNSCC [Rhee et al., Oncogene 2002; 21: 6598-6605], colorectal [Holcombe et al., Supra] Supraj, esophageal [TanaKa et al., Proc. Natl. Acad. Know. JdA ly98; 95: 10x64-10169] and gastric [Kirikoshi et al., Int. J. Oncol. 2u01; 19: 111-115], In addition, the overexpression of components of. Wnt signaling pathway such as Disheveliea fox associated with cancers such as ovary prostate cancer Wissman et Cancer

SCI I.Wissman et al., Supra], breast [Nagahata et al., 2003; 94: 515-518], mesothelioma [Uematsu et al., Cancer Res. 63: 4547-4551] and the cervix [Okino et al., Oncol Rep. 2003; 10: 1219-1223]. Overexpression of Frat-1 has been associated with cancers such as pancreatic, esoiagic, cervical, breast and gastric cancer. [Saitoh et al., Int. Oncol. 2002; 20: 785-789; Saiton et al., Int. Oncox 2001; 19: 311-315]. Axin loss of function mutations (LOF) was associated with hepatocellular cancer [satoh et al., Nature Genet. 2000; 24: 245-250; Taniguchi et al., Oncogene 2002; 21: 4863-4871] and medulloblastoma [Dahmen et al., Cancer Res. 2001; 61: 7039-7043; Yokota et al., Int. J. Cancer 2002; 101: 198-201].

In addition, a multitude of cancers have been associated with activation of β-catenin by disruption of the " degradation complex " such as β-cateruna function-gain mutations or loss-of-function mutations in APC. A reduction in β-catenin clearance results in higher amounts of functional β-catenin in the cell, which then produces increased transcription of the target genes, resulting in aberrant cello proliferation. For example, mutations in the gene encoding β-catenin (i.e., CTNNB1) were 49 Ρ 21403832Β1 associated with cancers such as gastric cancer [Clements et al., Cancer Res. 2002; 62: 3503-3506; Park et al., Cancer Res 1999; 59: 4257-4260], colorectal [Morin et al., Science 1997; 275: 1787-1790; Ilyas et al., Proc.

Natl. Acad. Know. USA 1997; 94: 10330-10334], intestinal carcinoid [Fujimori et al., Cancer Res. 2001; 61: 6656-6659], from the ovary [Sunaga et al., Genes Crom. Cancer 2001; 30: 316-321], pulmonary alaenocarcinoma [Sunaga et al., Supra], of the endometrium [Fukuchi et al., Cancer Res 1998; 58: 352 6-3528; Kobayashi et al., Japan. J. Cancer Res. 1999; 90: 05-59; Mirabelli-Primdahl et al., Cancer Res 1999; 59: 3346-3351], hepatocellular [Satoh et al., Supra .; Wong et al., Cancer 2001; 92: 136-145], hepatoblastoma [Koch et al., Cancer Res. 1999; 59: 269-273], medulloblastoma [Koch et al., Int. J. Cancer 2001; 93: 445-449], pancreatic [Abraham et al., Am. J. Pathol 2002; 160: 1361-1369], thyroid [Garcia-Rostan et al., Cancer Res. 1999; 59: 1811-1815; Garcia-Rostan et al., Am. J. Pathol 2001; 1,58: 987-996], prostate. [Chesire et al. , Prostate 2000; 45: 323-334; Voeller et al., Cancer Res 1998; 58: 2520-2523], melanoma [Reifenberger et al., Int. J. Cancer 2002; 10, 549-556], pilomatricoma [Chan et al. , Nature

Genet. 1999; 21: 410-413], Wilras tumor [Koesters et al., J. Pathol 2003; 199: 68-76], pancreatoblast.ornas [Abraham et al., Am. J. ratnoi 2001; 159: 1619-1627], liposarcomas [Sakamoto et al., Arch. Pathol. Lab Med. 2002; 126: 1071-1078], juvenile nasopharyngeal angiofibromas [Abraham et al., Am. J. Pathol. 2001; 158: 1073-1078], desmoide [Tejpar et al., Oncogene 1999; x8: 6615-6620; Miyoshi et al., Oncol. Res. 1998; 10: 591-594], synovial sarcoma [Saito et al., J. Pathol 2000; 192: 342-350]. While loss-of-function mutations have been associated with cancers such as colorectal [Fearon et al., Cell 1990; 61: 759-757; Rowan et al., Proc. Natl. Acad, Sci. USA 2000; 97; 3352-3357], Lanoma [Reifenberge et al., Int. J. Cancer 2002; 100 50 ΕΡ2403832Β1 54 9-55 6; Rubinfeld et al., Medulloblastoma [Koch et al. Huang et al., Am. J Desmoides [Tejpar et al., Alman et al., Am J. Pathol.

Science 1997; 275: 1790-1792], Int. J. Cancer 200 1; 93: 445- Pathol 2000; 156: 433-437] and Oncogene 1999; 18: 6615-6620; 1997; 15, 1: 329-334].

Other disorders associated with signaling d <

Wnt aberrant include, but are limited to, osteoporosis, osteoarthritis, a polymeric kidney. diabetes, schizophrenia, non-neurodegenerative proliferative diseases such as vascular diseases, heart disease, oncogenes, and as Alzheimer's disease.

Aberrant Wnt Signaling in Cancers and Leukemia Activation of the aberrant Wnt pathway through β-catenin stabilization plays a central role in tumorigenesis for many colorectal carcinomas. It is estimated that 80% of colorectal carcinomas (CRCs) harbor inactivation mutations in the APc tumor repressor, which takes into account uninterrupted Wnt signaling. In addition, there is great evidence to suggest that ga activation of Wnt pathway may be involved in melanoma, breast cancer, liver cancer, lung cancer, gastric cancer, and other cancers. Uncontrolled activation of the Wnt signaling pathway is also a precursor to the development of leukemia. pa experimental evidence that supports the oncogenic growth of both myeloid and lymphoid lines dependent on Wnt signaling. Signaling of Wnt f0j implied in the regulation of both chronic and acute forms of myeloid leukemia. The granulocyte-macrophage (GMP) progenitors of chronic myeloid leukemia patients and blastocyst crisis of patients resistant to therapeutic 51 ΕΡ2403832 apresentam1 present activated Wnt signaling. In addition, inhibition of β-catenin through the ectopic expression of Axin decreases the ability to re-cover leukemia cells in vitro, suggesting that precursors of chronic myeloid leukemia are dependent on Wnt signaling for growth and renewal. Overexpression of Wnt also causes GMPs to acquire similar long-term self-renewal stem cell properties, supporting the hypothesis that Wnt signaling is important for the normal development of bloodlines, but that aberrant Wnt signaling results , in the transformation of progenitor cells.

Recent studies also suggest that lymphoid neoplasms may also be influenced by Wnt signaling. Wnt-16 is overexpressed in pre-B cell leukemia cell lines that carry the E2A-PbX translocation, suggesting that Wnt autocrine activity may be delayed: ogenesis. Mc Whirter. Natl

Acad, Sci. USA 96: 11464-11469 (1999). The role of Wnt signaling in the growth and survival of normal B-cell progenitors still supports this notion. Reya et al., Immunity 13: 15-24 (2000); Ranheim et al., Blood 105: 2487-2494 (2005). The autocrine dependence of Wnt was also proposed to regulate the growth of multiple myeloma, a terminally differentiated B cell cancer. Derksen et al., Proc. Natl. Acad. Know. USA 101: 61z2-6127 5,2004). Primary myelomas and myeloma cell lines have also been found to be stably expressed (rstc), independently. of degradation). Although no mutation in the Wnt Signaling components was present, overexpression of several components, including Wnt-5A and Wnt-IOB, suggests that tumor dependence and self-renewal of cancer is not necessarily dependent on mutations appearing in only after activation of Wnt signaling, but instead constitutive of the route by itself. The transition from self-renewal, pluripotent stem cells to myeloid progenitors is achieved by the down-regulation of Wnt signaling. Reya et al., Nature 423: 409-414 (2003). Similarly, stable expression of β-catenin in lymphoid progenitors has restored multiple differentiation options, although such cells lack markers typically associated with the cell type. Baba et al, Immunity 23: 599-609 (2005).

Signaling of Aberrant Wnt in Neural Disorders onenn gemi

It was also observed that activation of Wnt signaling through β-catenin may increase the cycle and expansion of neural progenitors, and such loss of such signaling may result in a loss of compartment prog et al., Science 297: 365-369 (2002 ); Zechner et al., Dev. Bio. 258: 406-418 (2003). Just as normal activation of Wnt signaling can promote self-renewal of neuronal stem cells, activation of the aberrant Wnt pathway may be tumorigenic in the nervous system. Experimental evidence supporting this finding is the finding that medulloblastoma, a pediatric brain tumor of the cerebellum, contains mutations in both β-catenin and Axin, thus suggesting that medulloblastomas arise from primal parents that are transiently transformed into

SpOStâ cloning of uncontrolled Wnt. Zurawel et al., Cancer Res. 58: 890-899 (1998); Dahmen et al., Cancer Res. 61: 7039-7043 (.2001); Baeza et al., Oncogene 22: 632-636 (20U3). Thus, it is strongly suggested that inhibition of Wnt signaling by the Wnt antagonists of the invention may be an effective therapy in the treatment of various neuronal proliferative disorders, including brain tumors, such as gliomas, astrocytes, meningiomas, Schwannomas, pituitary tumors , primitive neuroectodermal tumors (TNEP), medulloblastomas, craniopharyngioma, pineal region tumors, and non-cancerous neurofibromatoses.

Wnt Signaling in Hematopoietic Stem Cells

Hematopoietic stem cells give oriaem to adult blood cells of the circulatory system in a process of progenitor cells committed to the multipotential hematopoietic stem cell line (HSC). It is also apparent that Wnt signaling contributes to self renewal and maintenance of HSC, and that dysfunctional Wnt signaling is responsible for several disorders resulting from HSC such as leukemias and various other blood related cancers. Reya et al., Nature 434: 843-850 (2005); Baba et al., Immunity 23: 599-609 (2005); Jamieson et al., N. Engl. J. Med. 351 (7): 657-667 (2004). Wnt signaling is usually reduced as the stem cells become committed myeloid progenitor cells. Reya et al., Nature 423: 409-414 (2003). Not only are Wnt ligands produced by HSC themselves, but Wnt signaling is also active, thus suggesting autocrine or paracrine regulation. Rattis et al., Curr. Opin. Hematol. 11: 88-94 (2004); Reya et al., Nature 423: 409-414 (2003). In addition, both β-catenin and Wnt3a promote self-renewal of murine HSCs and progenitor cells, while the application of Wnt-5A to human hematopoietic progenitors promotes the expansion of undifferentiated progenitors in vitro. Reya et al., Supra .; Willert et. 54, No. 2,403,832, A1, Nature 423: 448-452 (2003); Van Den Berg et al., Blood 92: 3189-3202 (1998). which epidermal stem cells and cells et al., supra; (1998); Sato et al., Cell 95: 605-2285-2298 (1999). of Wnt with the: can not be a

In addition to HSC, it is apparent embryonic, epithelial stem staminal cells are responsive or dependent on Wnt signaling for maintenance in a state of undifferentiated proliferation. Willert Korinek et al., Nat Genet. 19: 379-383 (1998); Sato et al Nat. Med. 10: 55-63 (2004); 614 (1998); Zhu et al., Developn

Therefore, inhibition of Wnt antagonists of the present invention in the treatment of disorders resulting from dysfunctional hematopoiesis such as leukemias and various blood related cancers such as myeloid and acute and chronic lymphoid leukemias, myelodysplastic syndrome and myeloproliferative disorders. These include myeloma, lymphoma (for example, Hodgkin's disease and non-Hodgkin's disease), chronic and progressive non-progressive anemia and symptomatic blood cell deficiencies, polycythemia vera, primary or primary thrombocythemia, idiopathic myelofibrosis, chronic myelomonocytic leukemia (CMML), mantle cell lymphoma, cutaneous T-cell lymphoma, Waldenstrom macroglobinemia.

Signaling of Wnt in Aging The Wnt signaling pathway may also play a critical role in aging and age-related disorders. As reported in Brack AS, et al., Science, 31 / (5839): 07-10 (2007), the muscle stem cells of aged mice were observed to convert from a myogenic to a fibrogenic lineage as they began to proliferate . This conversion is associated with a β2403832Β1 ΕΡ2403832Β1 signaling pathway of canonical Wnt activity in aged myogenic itores and may be by the Wnt inhibitors. In addition, the; of serum from aged mice bind to the increase in serum proxies

Frizziea, and may represent the syn- theorization of high cell numbers in aging cells. The injection of Wnt3A in

Dovem in regeneration reduced proliferation and immobilization or connective tissue deposition. The Wnt signaling pathway was further implicated in the aging process in studies using the accelerated aging Klotho rat model in which it was determined that Klotho protein interacted physically with Wnt inhibited proteins. Liu H, et al., Science, 317 (1987): 803-6 (2007). In a cell culture model, Wnt-Klotho interaction resulted in the suppression of biological Wnt activity whereas tissues and organs of Klotho deficient animals showed evidence of increased Wnt signaling.

Administration and Pharmaceutical Compositions

In general, the compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either separately or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending upon the severity of the disease, the age and relative health of the subject, the potency of the compound, and other factors. In general, satisfactory results are reported as being obtained systemically at daily dosages of from about 0.03 to 2.5 mg / kg body weight. A indicated daily dosage in a larger mammal, e.g. humans, is in the range of from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times daily or in delayed form . Unit dosage forms suitable for oral administration comprise from about 1 to 50 mg of active ingredient.

The compounds of the invention may be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions, topically , for example in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.

Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by means of mixing, granulating or coating methods. For example, oral compositions may be tablets or gelatin capsules comprising the active ingredient together with a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets together with c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and if desired, d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavorings and sweeteners. Injectable compositions may be solutions or suppositories of isotonic suspensions and suppositories may be prepared from fat emulsions or suspensions.

The compositions of the invention may be sterilized and / or contain as preservatives, preservatives, emulsifiers, osmotic pressure builders and / or buffers.

In addition, they may also contain other therapeutically valuable substances. Formulations suitable for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier may include pharmaceutically acceptable absorbable solvents to aid in passage through the skin of the host. For example, transdermal devices are in the form of a bandage, comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate control barrier for administering the compound to the skin of the host at a predetermined controlled rate over an extended period of time, and means for securing the device to the skin. Transdermal matrix formulations may also be used. Formulations suitable for topical application, for example to the skin and eyes, may be aqueous solutions, ointments, creams or gels well known in the art. This may contain solubilizers, stabilizers, tonicity enhancers, buffers and preservatives.

The compounds of the invention may be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, synergistic effects may occur when a compound of the invention is used in combination with a chemotherapeutic agent. Where the compounds of the invention are administered together with the co-administered compounds

In other embodiments, dosages will vary depending on the type of drug used, the specific drug used, the condition being treated, and so on. The invention also relates to pharmaceutical combinations, for example a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one coagent . The kit may comprise instructions for its administration.

Processes for preparing Compounds described in the present invention

In general, the compounds having Formula (1) may be prepared following any of the synthetic methodologies described in the Examples, infra. In the reactions described, reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, may be protected to prevent their undesired participation in the reactions. Conventional protecting groups may be used according to standard practice (see, for example, T. W. Greene and P. G. M. Wuts in " Protective Groups in Organic Chemistry ", John Wiley and Sons, 1991). Suitable leaving groups suitable for use in the disclosed synthesis methodologies include halogen leaving groups (e.g., chlorine or bromine), and other conventional leaving groups within the knowledge of those skilled in the art.

Compounds, including salts thereof, are also obtainable in the form of bidrates, or their crystals may include, for example, the solvent used for crystallization (present as solvates). Salts can usually be converted to compounds in the free form, for example, by treatment with suitable basic bases, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides such as such as potassium carbonate or sodium hydroxide. A compound of the invention in a base addition salt form may be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.). In view of the close relationship between the novel compounds in the free form and those in the form of their salts, including those salts which may be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds is to be understood as also referring to the corresponding salts, as appropriate.

Salts of compounds having a salt forming group may be prepared in a manner known per se. Acid addition salts of compounds of Formula (1), (2), (3), (4) or (5) may thus be obtained by treatment with an acid or a suitable anion exchange reagent. Pharmaceutically acceptable salts of the compounds described herein may be formed, for example, as acid addition salts with inorganic organic acids, from the compounds of Formula (1), (3), (4) or (5) with a basic nitrogen atom. Suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids include, but are not limited to, carboxylic, phosphoric, example, acetic acid, decanoic acid, lactic acid, fumaric acid sulphonic acid or sulfamic acids, propionic acid, octanoic acid, dodecanoic acid, glycolic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, β2403832Β1 hydroxymaleic acid, methylic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, italic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene disulfonic acid, 2-, 3- or 4-meth ylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propylsulfamic acid, or other organic protonic acids, such as ascorbic acid. For the purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example, picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are used (where applicable in the form of pharmaceutical preparations).

The compounds of the invention in non-oxidized form can be prepared from N-oxides of compounds as described herein by treatment with a reducing agent (for example, sulfur, sulfur dioxide, triphenyl phosphine, liter borohydride, sodium, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 ° C.

Prodrug derivatives of the compounds of the invention may be prepared by methods known to those skilled in the art with ordinary skill in the art (for example, for details see Saulnier et al., 61 (2001) 4033232, Bioorganic and Medicinal Chemistry Letters , Vol. 4, p.185). For example, suitable prodrugs may be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (for example, 1,1-acyloxyalkylcarboxylchloridate, para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention may be made by means known to those of ordinary skill in the art. A detailed description of applicable techniques d. the formation of protecting groups and their remixing can be P Ti 0 in T, W. Greene, " Protect ing Gro up S 1 n Organic Che: mistry " , 3rd edition, John Wiley and Sons, 99. The compounds of the invention may be prepared as their individual stereoisomers; by means of the reaction of a mis 3. racemic compound of the compound is an optically active resolving agent to form a diastereomeric pair of diastereomers, and the diastereomers are recovered in optically pure anti-ions. Resolution of enantiomers may be carried out by using diastereomeric derivatives of the invention compounds, or using the dissociable complexes (for example, diastereomers) : (S) - (-) -. The diastereomers have different physical properties (for example, melting points of 3.01 boiling points, reactivity, pt 'C *) and can be readily separated by taking advantage of these dif erations. The diastereomers can be separated by m-10 or by slight differences in pure resolution, as they would result in fractional crystallization, chromatography, solubility-based separation / resolution steps. The optically recovered enantiomer, together with the agent of any practical means other than racemization. A more detailed description applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, " Enantiomers,

Racemates and Resolutions ", John Wiley and Sons, Inc., 1981.

Briefly, the compounds of the invention may be made by a process as described in the Examples; and (a) optionally converting a compound of the pharmaceutically acceptable salt; m (b) optionally converting a salt form of the compound of the invention to a non-salt form; (c) optionally converting a compound form of the invention to an acceptable N-oxide; (d) optionally converting an N-oxide form of a compound of the invention to its non-oxidized form; (e) optionally solving an individual isomer of the compound of the invention of a mixture of isomers; (f) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and (g) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared in a manner analogous to the methods known in the art or as disclosed in Examples 63 to 48 hereinafter. One skilled in the art will appreciate that the above transformations are only representative of methods for the preparation of the compounds of the present invention and that other well-known methods may similarly be used. The present invention is further exemplified by the following and the Examples illustrating the preparation of the compounds of the invention and other compounds described herein.

Example 1 N- (6-methoxybenzo [d] thiazol-2-yl) -2- (4- (pyridin-4-yl) phenyl) acetamide (3)

DMF 3-2

HATLI DIEA

3-1

Compound 3 To a mixture of 3- (4- (pyridin-4-yl) phenyl) acetic acid 3-1 (45 mg, 0.21 mmol), 6-methoxybenzo [d] thiazol- 36 mg, 0.20 mmol), and DlEA (32 mg, 0.25 mmol) in DMF (0.5 mL) under stirring was added HATU (84 mg, 0.22 mmol). The solution was stirred for 2 hours before being subjected to reverse phase HPLC for purification to give compound 3 as a white solid. MS m / z 376.1 (M + 1); ] NMR 400 MHz (DMSO d 6) δ: 12.60 (s, 1H), 8.70 (m, 2H), 7.87 (m, 2H), 7.78 (m 2H), 7.72 ( d, 1H, J = 8.8Hz), 7.63 (d, 1H, J = 2.8Hz) 7.58 (im, 2H), 7.11 (dd, 1H, J1 = 8.8 H 2, J 2 = 2.4 Hz) F 2 O (s, 2 H), 3.86 (s, 3H). ΕΡ2403832Β1

Example 2 2- (3-methyl-4- (2-methylpyridin-4-yl) phenyl) -N- (4-phenylthiazol-2-yl) acetamide (24) tb______________________________________ tb > tb < tb > * $ ss »S * um? ΓΎΎ '? .............. (i.e. S

Step 1: To a suspension of 3-methyl-4-bromobenzoic acid 244 (2.15 g, 10 mmol) in toluene (15 mL, anhydrous) were added SO 2 Cl 2 (1.4 mL, ~ 1.9 eq ) and 3 drops of DMF at room temperature. The mixture was refluxed 2 hours with stirring. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (25 ml) and then at 0 ° C NEt 3 (2.2 ml) and TMSCHN 2 (Pg / ml × 2.0 M in hexanes) i. 0 n a d 0 s. After 12 hours of stirring, The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated to afford the title compound as a white solid (0.8 g). The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated to give crude intermediate 24-3. This crude product was added in small portions to a refluxing solution of NEt 3 (4.2 ml), PhCO 2 Ag (0.70 g) in t-butanol (50 ml) and toluene (20 ml) ) with stirring. After 1 hour reflux, the reaction mixture was cooled to room temperature. Activated carbon powder 65 ÅΡ240383261 was added to the reaction mixture which was then filtered through Celite. The filtrate was diluted with ethyl acetate (100 mL) and washed with brine. After being dried over Na 2 SO 4, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM-EtOAc (30: 1) as eluent to give the t-butyl ester 24-4.

Step 2: in DCM (16 ° C)

Ester 24-4 (810 mg, 2.84 mmol) was dissolved in trifluoroacetic acid (2 mL) and the mixture was stirred at r.t. room temperature: e. The DCM solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml) and this organic solution was extracted with Na2 CO3 solution (10% aqueous, 50 ml). The aqueous phase was acidified with HCl solution to pH 2 and the precipitate was extracted with ethyl acetate (50 ml). After being dried over Na2SO4, the organic solvent was evaporated to give 24-5 acid.

Step 3: To a mixture of compound 24-5 (92 mg, 0.4 mmol), 4-phenyl-2-aminothiazole 24-6 (76 mg, 0.44 mmol) and N-IATU (167 mg, 44 mol) in DMF (1.6 m) DIEA (100 uL, 0.58 mmol) was added and the mixture was stirred at room temperature overnight. It was then redistributed between ethyl acetate (50 ml) and water (40 ml). The organic phase was dried over Na2 SO4 > 4 and the solvent was evaporated. The residue was subjected to silica gel chromatography to give compound 24-7.

Step 4: A mixture of compound 24-7 (33 mg, 0.085 mmol), 2-methylpyridin-4-ylboronic acid (23 mg, 0.17 mmol), Pd (PPh3) 4 (9.8 mg, 0.0085 mmol) and K 3 PO 4 (36 mg, 0.17 mmol) in dioxane (0.6 mL) and water (0.06 mL) under argon was stirred at 96 ° C overnight. After cooling to room temperature, the reaction mixture was filtered through celite, diluted with ethyl acetate (50 ml) and diluted with water (50 ml x 2) and sat. Na 2 SO 4. After evaporation, the obtained residue was subjected to reverse phase HPLC to give the compound 24 as a white solid. MS m / z 400.14 (M + 1): 1 H NMR 400 MH + (DMSO-d 6) δ 12.58 (s, 1H), 8.56 (d, 1H, (M, 4H), 7.96 (m, 2H), 7.63 (m, 2H), 7.63 (m, 2H), 7.63 , 24 (d, 1H, J = 8.0Hz), 3.83 (s, 2H), 2.56 (s, 3H), 2.27 (s, 3H).

Example 3 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5-phenylpyridin-2-yl) acetamide (26)

To a sealed tube was added 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (2.2 g, 10 mmol), 2 Ethyl ester (26 ml) and potassium carbonate (50 ml) was refluxed for 2 hours at reflux temperature for 2 hours. 2 M Na 2 CO 3 (10 mL). The reaction mixture was sparged with nitrogen and stirred at 90 ° C for 10 hours. After being cooled to room temperature, the reaction mixture was diluted with 200 ml of ethyl acetate and washed with saturated sodium bicarbonate solution and then brine. The organic phase was dried over Na2SO4 and then taken to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 50% ethyl acetate in hexane to give ethyl 2- (4- (2-methylpyridin-4-yl) phenyl) acetate 26-2 as an oil. MS m / z 256.1 (M + 1).

The mixture of ethyl 2- (4- (2-methylpiperidin-4-yl) phenyl) acetate 26-2 (1.81 g, 7.1 mmol), Li (0.17 g, 1.11 mmol) in THF (30 mL), methanol (10 mL) and H2 O -20 mL; roy stirred. 60 ° C for 1 week. After being cooled to 0 ° C, the mixture was quenched with aq. 1 N at 0 ° C and then brought to dryness by rotary evaporation to yield 2- (4- (2-methylpylidin-4-yl) phenyl) acetic acid, 26-3 The product was used for the next step without purification MS m / z 228.1 (M + D.

Step 3: A mixture of 2- (4 - ((1-yl) phenyl) acetic acid 26-3 (50 mg, 0.2 mmol), amine (41 mg, 0.24 mmol) and hexafluoride), (7-azabenzothiazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU) (4.14 mg, 0.3 mmol) in 1.5 ml DMF was added N, N-diisopropylethylamine (DiEA, 1 4 ml, 0.6 mmol) at amorphous temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (o-phenylpindin-2-yl) acetamide as a white solid, MS m / z 380.17 (M + 1); 1 H NMR 400 MHz (DMSO-d 6) δ 1.0.84 (s, 1H), 8.0 (d, 1H, (d, 1H, J = 8.8 Hz), 8.04 (dd, 1H, J = (M, 5H), 3.66 (s, 2H), 2.46 (s, 3H), 7.44 (m, 5H), 7.45

Example 4 N- (5-phenylpyridin-2-yl) -2- (4- (pyridazin-4-yl) phenyl) acetamide (37)

To a sealed tube were added 4- (2-ethoxy-2-oxoethyl) phenylboronic acid 37-2 (310 mg, 1.5 mmol), 4-bromopyridazine 37-1 (158 mg, 1 mmol), Pd (PPh 3) 4 (70 mg, 0.1 mmol), toluene (4 mL), ethanol (1 mL) and 2M Na 2 CO 3 (1.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90 ° C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution and brine.

The organic phase was dried over Na2SO4 to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 50% ethyl acetate in hexane to give ethyl 2- (4- (pyridazin-4-yl) phenyl) acetate as pale yellow solid . MS m / z 243.1 (M + 1)

Step 2: 2- (4- (pyridazin-4-yl) phenyl] (150 mg, 0.62 mmol) and 1N NaOH (120 mg, 3 mmol) was mixed in dioxane (1.5 mL) and H2O (0.5 mL) and stirred at 80 ° C for 1 hour. After stirring to 0 ° C, the mixture was partitioned with aqueous solution of 1.34 N HCI to pH 1 and 69 ÅΡ2403832Β1 brought to dryness by rotary evaporation. The crude product was extracted with ethyl acetate (100 ml x 3). The combined organic phases were concentrated to give 2- (4- (pyridazin-4-yl) phenyl) acetic acid as pale yellow solid. MS m / z 215.1 (M + 1)

Step 3: To a mixture of 2- (4- (pyridazin-4-yl) phenyl) acetic acid 37-4 (43 mg, 0.2 mmol), 5-phenylpyridin-2-amine (41 mg, 0.24 ) and O- (7-azabenzotriazol-1-yl) -N, N, N'-ISM, N'-tetramethyluronium hexafluorophosphate (117 mg, 0.3 mmol) in DMF (1 mL) was added DIEA ml, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The crude product was purified by reversed-phase HPLC to give N- (5-phenylpiperazin-1-yl) -2-yl) -2-2- (4-pyridazinyl) -4- -yl) -phenyl) acetamide as white solid. MS m / z 317.1 (M + 1); 1 H NMR (400 MHz, CDCl 3) δ 9.41 (d, 1H, J = 9.44, m, 1H), 9.22 (dd, 1H, (d, 1H, J = 8.8 Hz), 1.44 (d, 1H, J = 2.4 Hz), 0.34 (d, 1H, J = 8.8 Hz) / Hz, J2 = 2.4 Hz). (M, 4H), 7.46-7.44 (m, 2H), 7.6-7.51 (m, 4H) (DMSO-d 6, 300 MHz): .delta. 70 EP24G3832B1

Example 5 2- (4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl) -N- (5-phenylpyridin-2-yl) acetamide (46)

Step 1: To a flask containing 3-trifluromethyl-4-bromobenzonitrile 46-1 (5.0 g, 20 mmol) was added water (20 mL) and concentrated sulfuric acid dropwise (20 mL). The reaction mixture was stirred at 100 ° C for 10 hours. After cooling to room temperature, the reaction mixture was poured into dichloromethane (150 ml) and water (100 ml). The mixture was neutralized with powdered sodium carbonate to pH 9. The aqueous layer was acidified with aqueous solution of 1N hydrochloric acid to pH 1, and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and then brought to dryness by rotary evaporation to 4-bromo-3- (trifluoromethyl) benzoic acid 46-2 as a white solid. MS m / z 269.1 (M + 1)

Step 2: To a solution of 4-bromo-3- (trifluoromethyl) benzoic acid 46-2 (1.35 g, 5 mmol) in THE (10 ml) was added 1 M BH 3 THF in THE (20 ml) slowly at 0 ° C. The mixture was warmed to room temperature and stirred for 4 hours. The reaction was quenched with water at 0 ° C. The entire solvent was evaporated and the residue redissolved in ethyl acetate (100 ml), washed with saturated aqueous NaHCO 3 solution, water and brine, dried over Na 2 SO 4, and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with 40% ethyl acetate in hexane to give (4-bromo-4-chloromethyl) phenyl) methanol 46- 3 as white solid mm / z 237.1 (M + 1)

Step 4 solution of 4-bromo-3- (trifluoromethyl) phenyl) methanol 46-3 (956 mg, 3.75 mmol) triethylamine (4.45 mg, 4.5 mmol) in: ) Of methanesulfonyl chloride (1.40 g, 3.75 mmol) in THF (1 mL) was added slowly at 10 ° C. The mixture was stirred for 1 hour. The solid was filtered and washed with ethyl ether, filtered, and evaporated to give 4-bromo-3- (trifluoromethyl) benzyl methanesulfonate as pale yellow solid. MS m / z 233.1 (M + 1)

Step 4: To a solution of 4-bromo-3- (trifluoromethyl) benzyl methanesulfonate 46-4 (1.295 g, 0.5 mmol) in ethanol (10 mL) was potassium (364 mg, refluxed for 2 hours). cooled to room temperature, the entire solvent was evaporated and a 6 mmol cyanide solution was added in water (2 ml). The mixture was hours. After the mixture has & dichloromethane (50 ml), washed with water and brine, dried over Na2SO4, and concentrated to dryness to give 2- (4-bromo-3- (trifluoromethyl) phenyl) acetonitrile 46-5 as dark brown oil, which was used for the following step directly. MS m / z 264.1 (M + 1)

A flask containing 2- (4-bromo-3-chloro-3,3-trifluoromethyl) phenyl) acetonitrile 46-5 (880 mg) was added water (4.5 ml) and acid. The reaction mixture was quenched with water (100 ml), and the resulting solution was neutralized with carbonate (100 ml), dried over anhydrous sodium sulfate of sodium powder to pH 12, treated with 1N aqueous HCl solution to pH around 2, and extracted with dichloromethane (50 ml x 3) .The combined organic layers were washed with brine, dried over Na 2 SO 4 and then taken up to dryness by rotary evaporation to give 2- (4-bromo-3- (trifluoromethyl) phenyl) acetic acid 46-6 as a pale yellow solid MS m / z 283.1 (M + 1)

Step 6: To a mixture of 2- (4-bromo-3- (trifluoromethyl) phenyl) acetic acid 46-6 (71 mg, 0.25 mmol), o-phenylpyridin-2-amine (64 mg, 0.38 mmol) and HATU (148 mg, 0.38 mmol) in DMF (1 mL) was added DIEA (12.5 mL, 0.75 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 ml), washed with saturated aqueous NaHCO 3 solution, water and brine, dried over Na 2 SO 4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 40% ethyl acetate in hexane to give 2- (4-bromo-3- (trifluoromethyl) phenyl) -N- (5-phenylpyridin-2 -yl) acetamide 46-7 as pale yellow solid, MS m / z 435.2 (M + 1)

To a sealed tube were added 2- (4-bromo-3- (trifluoromethyl) phenyl) -n- (5-phenylpyridin-2-yl) acetamide 46-7 (73 mg, 0.17 mmol), 2-methylpyridin-4-ylboronic acid (35 mg, 0.255 mmol), Pd (PPh3) 4 (12 mg, 0.017 mmol), toluene (0.8 mL), ethanol (0.2 mL) and 2M Na2 CO3 73 ΕΡ2403832Β1 ( 0.5 ml). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90 ° C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO 3 solution and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by means of rotary evaporation. The crude product was purified by reverse phase HPLC to give 2- (4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl) -N- (5-fluorophenyl) -2- 11) acetamide as white solid. MS m / z 448.1 (M + D; 1 H NMR 400 MHz: CDCl3) δ 8.4; 8-8.45 (m, 2H), 8.28 (d, 1H, J = 8.4 Hz), 7.92! dd, 1H, J1 = 8.4 Hz, J2 = 2.4 Hz), 7.75 (s, 1H), 7.61 (dd, 1H, J1 = 8.0 Hz, , 7.54-7.52 (m, 2H), 7.47-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.28 (d, 1 N, J = 7.6 Hz), 7.14 (s, 1 H), 7.10 (d, 1: H, J = 5.2 Hz), 3.86 (s, , 59 (s, 3H).

Example 6 2- (4- (1H-imidazol-1-yl) phenyl) -N- (5-phenylpyridin-2-11) acetamide (53)

Step 1: To a solution of 2- (4-iodophenyl) acetic acid, νmax 53-1 (816 mg, 3.14 mmol), 5-phenylpyridin-2-amine 53-21 ° 34 HATU (1.19 g, 3.14 mmol) in DMF (1 mL) was added DIEA (1.57 mL, 9.42 mmol) at room temperature at -78 ° C. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 ml), washed with saturated aqueous NaHCO 3 solution, water and brine, dried over Na 2 SO 4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 40% ethyl acetate in hexane to afford 2- (4-iodophenyl) -N- (5-phenylpyridin-2-yl) acetamide 53-3 as pale yellow solid. MS m / z 415.2 (M + 1)

Step 2: A mixture of 2- (4-iodophenyl) -N- (5-phenylpyridin-2-yl) acetamide 53-3 (41 mg, 0.1 mmol), imidazole (10 mg, 0.15 mmol), potassium phosphate (41 mg, 0.3 mmol), Cul (2 mg, 0.01 mmol) and L-proline (2.3 mg, 0.02 mmol) in DMSO (0.5 mL) was stirred under a dry argon atmosphere at 100 ° C for 10 hours. The crude product was purified by reverse phase HPLC to give 2- (4- (1H-imidazol-1-yl) phenyl) -N- (5-phenylpyridin-2-yl) acetamide as white solid. MS m / z 355.1 (M + 1); 1 H NMR 400 MHz (CDCl 3) δ 8.47-8.46 (m, 1H), 8.22 (d, 1H, J = 8.8 Hz), 7.99 (s, 1H) , 7.92 (dd, 1H, J1 = 16, 8 Hz, J = 7.4 Hz), 7.88 (d, 1H), 7.55-7.53 (m, 2H) ), 7.49-7.38 (m, 6H), 7.29 (s, 1H), δ 23 (s, 1H), 3.83 (s, 2H).

Example 7 N- (5- (1H-pyrazol-4-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide (65)

Compound 65 oh 75 ΕΡ2403832Β1

Step 1: To a solution of 2- (4- (2-methylpyridin-4-yl) phenyl) acetic acid 65-1 (300 mg, 1.3 mmol), 5-iodopyridin-2-amine (344 g, , 6 mmol) and HATU (590 mg, 1.6 mmol) in DMF (8 mL) was added DIEA (503 mg, 3.9 mmol) at room temperature. After being stirred at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 solution and then brine. The organic phase was dried over MgSO4. The solvent was removed and the crude product was purified by flash chromatography on silica gel to provide N- (5-iodopyridin-2-yl) -2- (4- (2-methylpyridin- -4-yl) phenyl) acetamide as white pearl solid. MS m / z 430.1 (M + 1).

Step 2: N- (5-Iodopyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide 65-2 (20 mg, 0.046 mmol) , 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (13.5 mg, 0.07 mmol) and Pd (PPh3) 4 (5 mg , 0.004 mmol) was mixed in toluene (3 mL) / ethanol (1 mL) / Na2 CO3 (2M, 1 mL). The reaction mixture was stirred at 90 ° C for 10 hours. The solvent was removed by rotary evaporation and the residue was removed by dissolving it in DMSO. The inorganic salt: filtration medium. The crude product in DMSO was purified by reverse phase HPLC to give N- (5- (1H-pyrazol-4-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl ) phenyl) acetamide as the white pearl solid. MS m / z 370.2 (M + 1). 76 ΕΡ2403832Β1

Example 8 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (6-morpholinopyridin-3-yl) acephiacetate (73)

A mixture of 2- (4- (2-methylpyridin-4-yl) phenyl) acetic acid 73-1 (40 mg, 0.18 mmol), 6-morpholinopyridin-3-amine (40 mg, , 22 mmol) and HCl (80 mg, 0.21 mmol) in 2 ml of DMF was added DIEA (â v ¤0.11 ægol-mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give the title compound 73 as a white solid. MS m / z 389.19 (M + 1); 1 H NMR (400 MHz, CDCl 3): δ 7.30 (s, 1H), 8.82 (d, 1H, , 8.35 (m, 1H), 8.24 (dd, 1H, J i -0.4 Hz, J2 = 6 Hz), 8.19 (dd, 1H, J2 = 10.0 Hz, J2 = 2 , 7.62 (d, 2 H, J = 9.6 Hz), 3.87 (s, 2H), 3.70 (m, 2H) , 75 (m, 4H), 3.66 (m, 4H), 2.80 (s, 3H).

Example 9 N- (5- (3-fluorophenyl) pyridin-2-yl) -2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) acetamide (74)

1-methanol 74-1 (1.57 g, 10 mmol) in dichloromethane (15 mL) was added thionyl chloride dropwise (3.6 mL, 50 mmol) at 0 ° C slowly. The mixture was stirred for 2 hours at room temperature, diluted with dichloromethane (100 ml) and water (100 ml), neutralized with powdered sodium carbonate to pH 8. The aqueous layer was further extracted with dichloromethane (50 ml) , The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation to provide 2-chloro-5- (chloromethyl) -3-methylpyridine as pale yellow solid which was used to the next etsipa directly. A mixture of 2-chloro-5- (chloromethyl) -3-methylpyridine 74-2 (1.64 g, 9.4 mmol), sodium cyanide ( 1.85 g, 37 mmol) and 15-crown-5 (0.1 mL, 0.47 mmol) in acetonitrile (30 mL) was stirred at 40 ° C for 4 hours. After. The mixture was cooled to room temperature, the solvent was evaporated and the residue was redissolved in ethyl acetate (100 ml). washed with water and brine, dried over Na2 SO4, and concentrated to pale yellow (6-chloro-5-methylpyridin-3-yl) acetonitrile as a pale yellow liquid which was used for the following step without further purification. MS m / z 167.1 (M + 1) 78 ΕΡ2403832Β1

Step 3: To a flask containing 2- (6-chloro-5-methylpyridin-3-yl) acetonitrile 74-3 (1.12 g, 6.75 mmol) was added water (9.0 ml) and concentrated sulfuric acid (9.0 ml) was added dropwise. The reaction mixture was stirred at 100 ° C. for 4 hours. After being cooled to room temperature, the reaction mixture was poured into water (100 ml). The resulting solution was neutralized with powdered sodium carbonate to pH about 3, and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and then brought to dryness by rotary evaporation. To give 2- (6-chloro-5-methylpyridin-3-yl) acetic acid as pale yellow solid, which was used directly for the next step. MS m / z 186.1 (M + 1) A mixture of 2- (6-Chloro-5-acetic acid 74-4 (222 mg, 1.2 mmol), 5-amino- ) And HATU (684 mg, (5 mL) was added DIE LA (600 mL, 3.6 mmol).

Step 4: Methyldiphen-3-yl) phenylpyridin-2-ol 1.8 mmol) in DMF (5 mL) mmol) at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 ml), washed with saturated aqueous NaHCO 3 solution, brine, dried over sodium sulfate. Na 2 SO 4, concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 40% ethyl acetate in dichloromethane to give 2- (6-chloro-5-methylpyridin-3-yl) -N- (5- (3- fluorotenyl) pyridin-2-yl) acetamide 74-5 as dark yellow. MS m / z 356.1 (M + 1).

Step 5: To a reaction tube containing 2- (6-chloro-5-methylpyridin-3-yl) -N- (5- (3-fluorophenyl) pyridin-2-yl) acetamide 74-5 (54 mg, , 15 mmol), 4- (tributylstanyl) pyridazine (55 mg, 0.15 mmol) and Pd (PPh 3) 4 (16 mg, 0.015 mmol) under argon added DMF (0.8 mL). The mixture was stirred at 120 ° C for 10 hours. The crude product was purified by reverse phase HPLC to give N- (5- (3-fluorophenyl) pyridin-2-yl) -2- (5-methyl-6- (pyridazin-4-yl) pyridin-3 -yl) acetamide as white solid. MS m / z 400.1 (M + 1); 1 H NMR (CDCl 3) δ 9.42 (dd, 1H, J 1 = 1.4 Hz, J 2 = 1.2 Hz), 9.29 (dd, 1H, J 1 = 10 (D, 1H, J = 1.6 Hz), 8.46 (d, 1H, J = 1, 6 Hz), 8.28 (d, 1H, J = 8.8, δ), 7.90 (dd, 1H, J 1 = 17, (Hz, J 2 = 2.4 Hz) d, In, U 1, 6 Hz), 7.70 (dd, 1H, J 1 = 10.8 Hz, T), δ 44-7.39 (m, 1H ), 7.32-7.30 (m, 1H), 7.25-7.21 (m, 1H), 7.09-7.04 (m, 1H), 3.82 (s, 2H), 2.44 (s, 3H).

The title compound was prepared as a white solid (0.8 g) as a pale yellow solid. EXAMPLE 11 5- (Pyrazin-2-yl) -2- (2 ', 3-diraepyl-2,4-bipyridin-5-yl) yl) pyridin-2-yl) acetamide (86) Bfr-3?,? 1?,? 1?

(1), (2), (2) and (3). - - - - - - - - - - - - - - - - - - - - - - - - - 1 s í í • • • • • •. : Γίίρνν. 1, 2, 3, 4, 4, 5, 6, 7,

To a sealed tube was added 5- (4,4,5,5-3,2-dioxaborolan-2-yl) pyridin-1-yl) -2-iodo-pyrazine (2.2 g, 06 g, 86-1.0 mmol),

Pd (PPh 3) 4 (57 / mg, 0.5 mmol), toluene (70 ml), ethanol (15 80 ΕΡ2403832Β1 ΕΡ2403832Β1: ν ml) and 2 Μ Na2 CO3 (15 ml). the reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90 ° C for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue redissolved in dichloromethane (200 ml) and treated with 1 M aqueous HCl solution (50 ml). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting suspension was extracted with ethyl acetate (100 ml x 3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated to give 5- (pyrazin-2-yl) pyridin-2-amine as a white solid. only white. NMR (DMSO-d 6) δ 9.12 (d, 1H, J = 1.6 Hz), 8.73 (m, 1H) (Dd, 1H, J = 8, 8 Hz, J = 2, 8 Hz), 8.12 (dd, 1H, J = 4 Hz), 6.55 (d, 1H, 8.8 Hz), 6.46 (s, 2H)

Step 2: To a sealed tube was added 5-bromo-2-chloro-3-methylpyridine 86-4 (4.69 g, 22.2 mmol), 0.5 M (2-tert-butoxy-2-oxo ethyl) chloride (II) in 86-5: 1 ether, 25 mmol), Pd (dba) 2 (262 mg, 0.45 mmol), ζ) -phos (320 mg, ), and THE (75 ml). The reaction mixture was bubbled with nitrogen for 10 min at 70 ° C for 4 hours, after cooling to the evaporated temperature and the residue was ethyl, washed with water and dried to dryness by the crude product was flash chromatographed on silica gel and hexane in hexane to give 2- the solvent was redissolved in brine, dried over Na2 SO4, and evaporated through a rotary evaporation medium. The residue was purified by chromatography on silica gel eluting with 20% of ethyl (6-chloro-5-methylpyridin-3-yl acetate as a red oil, MS m / z 422), tert-butyl acetate 86-6 (M + 1) ), N- (5-chloro-5-methyl-pyridin-3-

Step 3: A mixture of 2 μl. . (7.8 g, 32 mmol) and tert-butyl TFA (32 μl) and DCO (32 mL) was added at room temperature for 4 hours. 3 hours. The solution had ρρΗ adjusted to about 12 by sodium carbonate and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by 1N aqueous HCl solution and stirred for 15 minutes. The suspension was extracted with dichloromethane (100 mL X3). The combined organic phases were washed with water and brine, and dried over Na 2 SO 4 and then dried to give 2- (6-chloro-5-methylpyridin-3-yl) -cyclohexanecarboxylic acid as the yellow solid pallium MS m / z 186.1 (M + 1); (D, 1H, J = 2.0 Hz), 7.55 (d, 1H, U-2.0 Hz), 3.63 (s, OH), 2.38 (s, 3H). Step 4: A mixture of 2- (R) -chloro-5-methylpyridin-3-yl) acetic acid 86-7 (3.0 g, 16.2 mmol), 5- (pyrazin- yl) pyridin-2-amine 86-3 (2.80 g, 16.2 mmol), 1,3-dicyclohexylcarbodiimide (4 g, 19.44 mmol) and 4-

(dimethylamino) pyridine (324 mg, 3.24 mmol) in DMF (45 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered to remove solid. The filtrate was diluted with ethyl acetate, washed with water and brine, dried over N3.2 SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 5% methanol in dichloromethane to give 2- [6-chloro-5-methoxypiperidin- (1-pyrazin-2-yl) pyridin-2-yl) acetamide 86-8 as pale yellow solid. MS m / z 340.2 (M + 1); (DMSO-d 6) δ 11.09 (s 1H), 9.31 (d, 1H, J = 1.6 Hz) (m, 1H), 8.51 (dd, 1H, J1 = 6.6 Hz, J2 = 2.4 Hz), 8.21 (m, 2H), 7.76 (d, 1H, J = 1.6 Hz), 3.82 (s, 2H), 2.33 (s, 3H).

Step 5: To a reaction flask containing 2- (6-chloro-5-methylpyridin-3-yl) -N- (5- (3-fluorophenyl) pyridin-2-yl) acetamide 86-8 (3.34 (3.47 g, 9.4 mmol), 0.94 mmol) under argon was added DMF mixture for stirring at 120 ° C for 10 minutes. The solution of 1N KF aqueous solution was added to the mixture for 15 minutes after being cooled to room temperature, the solid formed (1: 1) was collected by filtration and further purified by flash chromatography on silica gel, eluted with 10% methanol in dichloromethane to give 2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) - N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (Compound 86) as a white solid (M + 1); 1 H NMR (400 MHz, DMSO-d 6: δ 1.13 (1H), 9.31 [(1H, J = 1.6 Hz), 9.11 (d, 1H) (m, 1H), 8.62 (d, 1H, 2.8 Hz), 8.4 (m, 3H) (D, 1H, J = 8.8 Hz), 7.73 (d, 1 H, J = 8.8 Hz) 1H), 7.35 (dd, 1H, J1 = 4.8 Hz, J2 = CH3), 3 to 7 (s, 2H) ), 2.34 (s, 3H).

Example 11 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) acetamide (111) 83 ΕΡ2403832Β1 < ; / ** X 'r%. / XV% M rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά Ά. eur-lex.europa.eu eur-lex.europa.eu

UVS a Sít | A. · Ά &quot; Th- * v Λ s' · ';' · < (1), (2), (2), (2) and (3)

'V Hí η * & .

FIG. cv; ss,. ZL ..... *. rvV &lt; tb &gt;. &quot;

UM 1

Step 1: Into a sealed tube was added 5-bromo-2-nitropyridazine 111-1 (2.39b 11.4 mmol), 1- (piperazin-1-yl) ethanone 111-2 , 6 g, 12.8 mmol), triethylamine (4.8 mL, 34.2 mmol) and DMSO (5 mL). The reaction: was heated to 120 ° C and stirred for 16 hours. The reaction was cooled to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 ml of ethyl acetate. The solid was collected by filtration and washed with a small amount of ethyl acetate to give 1- (4- (6-nitropyridin-3-yl) piperazin-1-yl) ethanone as a mono . i o. the light yellow. MS m / z 251.1 (Me1).

Step 2: To a flask was added 1- (4- (6-nitropyridin-3-yl) piperazin-1-yl) ethanone 111-3 (2.6 g, 10.4 mmol), Pd (0.5 g) and methanol (50 ml). The reaction was stirred for 4 hours under an atmosphere of hydrogen for 84 Å † 24040321 and the hydrogen flask. The reaction was carried out as a single 3 v. and the solid was removed by means of removal of the residue by means of evaporation of an anthar with az

extraction. 0 s o .1 ve »J rotating. The crude product was purified by flash chromatography on silica gel to give 1- (4- (6-

aminopyridin-3-yl) piperazin-1-yl) ethanone 11] -4 as a white beige solid- MS m / z 221.1 (M + 1). 1 H NMR 400 MHz (DMSO-d 6) δ 7.62 (d, 1H, J = 2.8 Hz), 7.20 (dd, 1H, 8.8 Hz, J2 = 2.8 Hz) (S, 3H), 2.93 (t, 3H, J = 2Hz), 3.95 (m, 2H, J = 5.2 Hz), 2.86 (t, 2 J

Step 3: Into a sealed tube, a mixture of 2-chloro-5-iodobenzonitrile 111-5 (i, 30 g, 5 mmol), 0.5 M (2-tert-ethoxy-2-oxoethyl) zinc chloride (TI ) 111-6 in ether (n ml, 5.5 mmol), β-phos (178 mg, 0.25 mmol) , and Xhp, n. . . (100 ml) under argon was stirred at 70 ° C for 18 hours. cooling to room temperature, the redissolved solvents were evaporated and the residue dried (Na2 SO4), washed with water and brine, dried over Na2 SO4. , and concentrated to dryness by rotary evaporation. The crude product was purified by chromatography. , η · X f f on silica gel, eluted with 3% EtOAc. In hexane to give 2- (4-chloro-3-cyanophenyl) acetate r] p, - +. As a brown oil. MS m / z 252 x 1 (M + 1).

Step 4:

A mixture of tert-butyl 2- (4-chloro-3-cyanophenyl) acetate (572 mg, 2.28 mmol), 2-methyl-4- (t- (8/0 mq, 2.28 mmol) and Pd (PPh) (2.00 mg, 0.2 mmol) and DMF (9 ml) 1 H NMR (300 MHz, CDCl3) Î': 0.8 (s, 3H), 1.05 (s, 3H). and evaporated to dryness under argon. After the Lens, the mixture was dried with Na2 SO4 saturated sodium sulfate, and evaporated in vacuo. (3-chloro-4- (2-methylpyridin-4-yl) -piperidin-4-yl) -piperazine The crude material was purified by flash chromatography (dl-yl) phenyl) acetate -9 as a yellow oil MS m / z 309.2 (M + 1).

Step 5: A mixture of tert-butyl 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) acetate 111-9 (656 mg, 2.13 mmol) and TFA (2 mL) in DCM (2 ml) was stirred at room temperature for 3 hours. The solution had the pH adjusted to around 12 by NaCl and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by solution to 1N aqueous HCl and detected for 15 minutes. The solvents were evaporated and the remaining solid was extracted with 20% methanol in ethyl acetate and filtered to remove the insoluble. The filtrate was concentrated to dryness by rotary evaporation to give a sticky solid containing 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) acetic acid, which is used directly for the following step, MS m / z 253.1 (M + 1).

Step 6: To a mixture of 111-10 acid (150 mg crude from the above containing about 25 mg, 0.1 mmol), 1- (4- (6-aminopyridin-3-yl) piperazin- yl) ethanone (22 mg, 0.1 mmol) and N - N, N '- and overnight. Water (30 ml) and ethyl acetate was dried over Na 2 SO 4 and concentrated to tetramethyluronium hexafluorophosphate (HATU, 40 mg, 0.105 m). DMF (1 ml) and diisopropylethyl amine ( DIeA, 38.1 mg, 0.3 mmol) and the mixture was stirred at room temperature overnight. Then it was dried through rotary evaporation. The oily residue was treated with reverse phase preparative HPLC and silica gel chromatography to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4 - (2-methanesulfonyl-4-yl) phenyl) acetamide (Compound 111) as a white solid. MS m / z 455.3 (M + 1).

Example 12 M- (5- (pyrazin-2-yl) pyridin-2-yl) -2- (4- (pyridazin-4-yl) -3- (trifluoromethyl) phenyl) acetamide (118)

DMF, 120 ° C compound 118

Step 1: To a mixture of 2- (4-bromo-3- (trifluoromethyl) phenyl) acetic acid 46-6 (128 mg, 0.5 mmol), 5- (pyrazin-2-yl) pyridin-2-amine 86-95 (95 mg, 0.55 mmol) and o- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU, 214 mg, 0.55 mmol) in DMF (2 ml) was added diisopropylethyl amine (DIEA, 250 ml, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous NaHCO 3 solution, water and brine, dried over Na 2 SO 4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 5% methanol in dichloromethane to give 2- (4-bromo-3- (trifluoromethyl) phenyl) -N- (5- (pyrazin-2- yl) pyridin-2-yl) acetamide 118-1 as pale orange solid. MS m / z 438.2 (M + 1) 87 ΕΡ2403832Β1

Step 2: To a reaction tube containing 2- (4-bromo-3- (trifluoromethyl) phenyl) -N- (5-pyrazin-2-yl) pyridin-2-yl) acetamide 118-1 ( 53 mg, 0.12 mmol), 4- (tributylstanyl) pyridazinyl S ' 0.14 mmol) and Pd (PPh 3) 4 (14 mg, 0.012 mmol) under argon was added DMI 11 (0.6 mL). The mixture was cooled to 120 ° C for 10 hours. The crude product, which was a solution, was subjected directly to reverse phase HPLC to give N- (5- (pyrazin-2-yl) pyridin-2-yl) -2- (4- (pyridazin-4 (1-trifluoromethyl) phenyl) -6-methoxy-2-oxopyridine. As the solid B rani 00. MS m / z 437.1 (M + 1); 1 H NMR 400 MH z (DMSO-d 6) δ 11 (s, 1 H), 9.35 (dd, 2H), δ 31 (d, 1H), 9.27 (s, 1H), 9 (D, 1H), 8.52 (dd, 1H), 8.23 (d, 1H), 7.09 (d, 1H) , 1H), 8.22-7.75 (m, 9H), 7.9 (1H, s), 4.00 (s, 2H).

Example 13 N- (2,3'-bipyridin-6'-yl) -2-yl) acetamide (124), 3-dimethyl-2,4'-bipyridin-5- 44 ° C. &quot; * Or-Ç &gt; 4 1 .... 8 'X. vW · il 1 |  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ

, 04-p &quot; p T

mo; N &quot; ^ f:

To a reaction tube was added 5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (220 mg, 1.00 mmol), 2-iodopyridine (205 mg, 1.00 mmol), Pd (PPI 13) 4 (57.7 mg, 0.05 mmol) and K 3 PO 4 (424 mg, 2.00 mmol). The tube was evacuated and filled again with argon. Dioxane (3.0 mL) and water (0.3 mL) were added and the mixture was heated at 96 ° C overnight. After cooling to room temperature, the reaction mixture 88 ÅΡ2403832Β1 was cold. through celite (washed with ethyl acetate) and concentrated by evaporation. The residue was redistributed between ethyl acetate (40 mL) and 0.1 N HCl solution (40 mL). the aqueous acid phase was further extracted with ethyl acetate (40 ml x 2) and treated with Na 2 CO 3 to have a pH around 9 and concentrated by evaporation of water. The solid residue was extracted with refluxing ethyl acetate (40 mL) to give 2,3'-bipyridin-6'-amine (124-1) which is used for reaction without further purification.

Step 2. A mixture of 2- (6-Chloro-5-methylpyridin-3-yl) acetic acid 74-4 (57 mg, 0.31 mmol), 2,3'-bipyridin-6'-amine 124-1 (75 mg, 0.36 mmol) and 4- (dimethylamino) pyridine (6 mg, 0.06 mmol) in DMF (1.2 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered through celite, washed and diluted with ethyl acetate (30 ml) and extracted with water (930 ml x 2). The organic phase was dried over Na 2 SO 4 and concentrated by evaporation. The residue was subjected to silica gel column chromatography with ethyl acetate as eluant to give N- (2,3'-bipyridin-6'-yl) -2- ( 6-chloro-5-methylpyridin-3-yl) acetamide as a white solid.

Step 3. To a reaction tube were added 5-N- (2,3'-bipyridin-6'-yl) -2- (6-chloro-5-methylpyridin-3-yl) acetamide 124-2 (52 mg, 15 mmol), 2-methyl-4- (trifluoromethyl) pyridine (115 mg, 0.3 mmol), and Pd (PPh 3) 4 (35 mg, 0.03 mmol). The tube was subjected to vacuum and

Filled with argon again. DMF (1.0 mL) was added and the mixture was warmed to. oil bath at 118 ° C overnight. After being cooled to room temperature, the mixture was filtered through celite, washed and diluted with ethyl acetate (30 ml) and extracted with 0.1 N HCl solution (30 ml). The acidic aqueous phase was treated with Na2 CO3 (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over Na2 SO4 and evaporated. The residue was chromatographed on silica gel on a column of% MeOH in DCM and eluant to give N- (2,3'-bipyridin-6'-yl) -2- ( 2 ', 3-di-tert -butyl-2,4' -bipyrid-5-yl) acetamide as a white solid. 1 H i i. -L. Oa p v Ay j .. an co. MS m / z 396.3 (M + D; 1H: NMR 400 MH z (CDCl3): δ 8.93 CO 009 (m, 1H), 8.72-8.66 (m, 1H); (Bs, 1H), 7.76 (m, 2H), 8.59 (d, 1H), 3.51 (dr 1H), 8.37-8.29 (m, 1 H), 7.65 (d, 1 H), 7.33 (bs, 1 H), 1.30 - 7.24 (m, 1 H), 3.81 (s, 2H), 2.63 (s, 3H), 2.38 (s, 3H)

Example 14 tert -Butyl 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-ylpiperazine-1-carboxylate (125)

Boc Boc f e

125-3 125-4 Boc

26-3

HÁTU DIEÂ

Step 1: To a sealed tube was added 5-bromo-2-nitropyridine 125-1 (5.1 g, 25.2 mmol), tert-butyl piperazine-1-carboxylate 125-2 (4.7 g, , 2 mmol), DIEA (12 mL, 75 mmol) and DMSO (20 mL). The reaction was heated to 120 ° C and stirred for 16 hours. The reaction was cooled to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 ml of ethyl acetate. The solid was collected by filtration and washed with a small amount of ethyl acetate to give tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate as pale yellow solid. MS m / z 309.2 (M + 1).

Step 2: To a round bottom flask was added tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate 125-3 (3.4 g, 11 mmol), Pd / 5 g) and methanol (100 ml). The reaction was stirred for 4 hours under hydrogen atmosphere by the union of a hydrogen flask. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate as purple solid. MS m / z 279.2 (M + 1).

Step 3: To a mixture of 2- (4- (2-methylpyridin-4-yl) phenyl) acetic acid 26-3 (1.1 g, 4.8 mmol), 4- (6-aminopyridin-3-yl ) piperazine-1-carboxylate 125-4 (1.3 g, 4.6 mmol) and O- (7-azabenzotriazol-1-yl) -N, N ', N', N'-tetramethyluronium hexafluorophosphate (HATU) (2.0 g, 5.3 mmol) in DMF (15 mL) was added DIEA (2.4 mL, 13.8 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO 3, then brine, dried over Na 2 SO 4. The solvent was removed by rotary evaporation to give 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1 1 H NMR (DMSO-d6) δ 8.10.55 (s, 1H), 8.56 (d, 1H) , 8.03 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.74 (s, 1H), 7.66 (d, 1H), 7.51 (d, 2H), 7.42 (m, 1H), 3.75 (s, 9H), 3.08 (b, 2 m) s, 4H), 2.51 (s, 3H), 1.42 (s, 9H).

Example 15 2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (130)

86-8 compound 130

Step 1: To a reaction tube containing 2- (6-chloro-5-methylpyridin-3-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide 86-8 (70 mg (0.29 mL, 0.21 mmol), 4- (tributylstanyl) pyridine (79 mg, 0.21 mmol) and Pd (PPh 3) 4 (22 mg, 0.021 mmol) under argon was added DMF (0.9 mL). The mixture was stirred at 120 ° C for 10 hours. The solution and crude DMF was purified by reverse phase DOP to give 2- (5-methyl-6- (pyridazin-4-yl) pyridin-3-yl) -N- (5- (pyrazin- 2-11) pyridin-2-yl) acetamide as white solid. MS m / z 214.1; (DMSO-d 6) δ 11.15 (O r 1H) 9.47 (d, 1H), 9.34 (dd, 1H), 9.31 (d, 1H), 8.62 (d, 1H), 8.56 (m, 1H), 8.52 (dd, 1H), 8.21 (d, 1H), 7.92 (dd, 1H), 7.79 (s, 1H), 3.90 (s, 2H), 2.42 (s, 3H).

Example 16 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide (131) 92 ΕΡ2403832Β1 Bgc

and-

Step 1: To the solution of tert-butyl 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1-carboxylate (125) , 5 g, 3 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction was stirred for 2 hours. The excess TFA and solvent was removed by rotary evaporation to give 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5- (piperazin-1-yl) pyridin-2-yl) acetamide 131-1. The compound was used for the next step without further purification. MS m / z 388.2 (M + 1).

Step 2: The solution of 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5- (piperazin-1-yl) pyridin-2-yl) acetamide 131-1 (20 mg, , 5 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and acetyl chloride (3.9 mL, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- ( 2-methylpyridin-4-yl) phenyl) acetamide as white solid. MS m / z 430, r 2 (M + 1); [1 H NMR 400 MHz (DM.SO- d 6) δ 10.50 (s, 1H), 8.45 (d, 1H), 7. 97 (d, 1H), v, 87 (d, 1H), 7.71 (d, 2H), 7.57 (s, 1H), 7.49 (d, 1H)! (d, 9H), 3.37 (dd, 1H), 3.68 (s, 2H), 3.52 (m, 4H) , Δ (t, 2H), 2.48 (s, 3H), 1.97 (s, 3H)

Example 17 Methyl 4- (6- (2- (4- (2-methylpyridin-4-yl) phenyl) acetamido) pyridin-3-yl) piperazine-1-carboxylate (132)

The solution of 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5- (piperazin-1-yl) pyridin-2-yl) acetamide 131-1 (20 mg, 0.05 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and methyl chloroformate (5.2 mg, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- ( 2-methylpyridin-4-yl) phenyl) acetamide as white bead solid. MS m / z 446,: 2 (M + 1); 1 H NMR (DMSO-d 6) δ 10.55 (s, 1H), 8.72 (br, 1H), 8.18 (s, 1H), 8.08 (m, 1H) (D, 1H), 7.50 (d, 2H), 7.35 (dd, 1H), 3.72 (s, 2H) ), 3.54 (s, 3H), 3.43 (t, 4H), 3.03 (t, 3H), 2.65 (s, 3H). Example 18 2- (3-Methyl-4- (pyridazin-4-yl) phenyl) -N- (5- (pyridazin-4-yl) pyridin-2-yl) acetamide (134) 94 ΕΡ2403832Β1V4r *

$ &amp; / R &lt; 1 &gt; &gt; ^ '! s K

t '&gt; &quot; V / W &quot; -TB-- &quot; To a reaction tube were added (R) Δ RR - r tt -> (57.7 mg, trametil-1,3,2-dioxaborolan-2-yl) pyridin-2-one mmol), 4-bromopyridazine (50 mg, 159 mg, 1.00 mmol), 5 mmol) and K 3 PO 4 (424 mg, 2.00 mmol).

A 9 6 0 C at night. After cooling to room temperature, the reaction mixture was washed with acetate and evaporated to dryness (5% methanol in dichloromethane-4-yl) pyridine-2-amine 134- (855 mg, 3.0 mmol), 4- (1162 mg, 3.15 mmol), Pd (PPh 3) 4 10 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white solid (0.25 ml) and water (0.3 ml) was refluxed for 2 hours. (173 mg, 0.15 mmol) in dichloromethane (5 ml) was added dropwise and the residue was partitioned between ethyl acetate and dichloromethane as eluent. and DMF of argon at 118Â ° C at room temperature, evaporation of DMF, redissolved in ethyl acetate (50 ml) and washed with water (50 ml x 2) After being dried over Na 2 SO 4 and concentrated by evaporation, the mixture was subjected to to chromatography (1: 1) as eluent to give tert-butyl 2- (3-methyl-4-pyridazin-4-yl) phenyl) acetate as starting material. .it's the. -2 obtained in step. was added trifuroacetic acid (TF A, 3 ml) overnight. After being concentrated, aqueous Na 2 CO 3 solution (30 mL) was redistributed. each to about pH 2 with ethyl acetate (40 mL) was evaporated to give (2-methylphenyl) cyclohexane as a non-puri fi ed

The aqueous phase was acidified to (3-methyl-4-pyridazin-4-solid which is used for further reaction.

A mixture of 5- (pyridazin-4-yl) pyridin-2-amine 134-1 (53 mg, 0.31 mmol), 2- (3-methyl-4- (pyridazin- phenyl) -acetic acid ethyl ester 134-3 (73 mg, 0.32 mmol), (1.0 g, 0.3 mole) and the solution treated with 3.2 CO 3 (40 ml) The pH is about to about 1 ° C (30 ml x 2). HATU (122 mg, 0.32 mmol) and DIEA (80 æL, 0.46 mmol) in DMF) was stirred at room temperature overnight and partitioned between ethyl acetate (40 mL) and aqueous HCl solution The residue was subjected to reversed-phase HPLC to yield 2- (3-methyl-4- (pyridazin-4-yl) -propionic acid, yl) phenyl) -N- (5- (pyridazin-4-yl) pyridin-2-yl) acetamide as white bead solid MS m / z 383.2 (M + 1).

Example 19 2- (6- (4-Acetylpiperazin-1-yl) pyridin-3-yl) -N- (5- (3-fluorophenyl) pyridin-2-yl) acetamide (140) 96 ΕΡ2403832Β1 / -OH Gly- /) - / + h2n ~

Step 1. A mixture of z - (1-chloropyridin-4-yl) acetic acid (521 mg, 3.03 mmol), 5- (3-fluorophenyl) pyridin-2-one (5.0 mg, 3.03 mmol ), HET (1250 mg, 3.29 mmol) and DIE (784 mL, 4.50 mmol) in DMF (10 mL) was stirred at room temperature overnight. Most of the DMF was removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with 3% Na 2 CO 3 solution (30 mL) and water (50 mL), and dried over Na 2 SO 4. After concentration by evaporation. the residue was chromatographed on silica gel column to give 2- (6-chloropyridin-3-yl) -N- (5- (3-fluorophenyl) pyridin-2-yl) acetamide 140- 1.

Step 2. Yl) acetamide 140-1 (100 mg, 0.29 mmol) was heated with 1- (piperazin-1-yl) -yl) ethanone (0.8 mL) at 108 ° C for 4 hours. The mixture was dissolved in EtOAc (30 mL), washed with water (40 mL), and dried over Na 2 SO 4. After concentration by evaporation, the residue was subjected to reversed-phase HPLC to provide 2- (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) -N- (5- (3-fluorophenyl) ) pyridin-2-yl) acetamide as solid. 97 ΕΡ2403832Β1

Example 2 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5- (3-oxopiperazin-1-yl) pyridin-2-yl) acetamide (141)

Et a pa 1: a sealed tubing has been added. (0.11 g, 5 mmol), piperazine-2-on to 1 41-Z (0.6 g, r mmole 1), DIEA ( 1.8 ml, 18 mmole) and DMS (3 (6 ml) in the reaction from 0Â ° to 1Â ° C is 120Â ° C and stirring for 16 hours. cooled to the initial temperature, and the precipitate evaporated to give the residue. The residue was evaporated in vacuo to give the residue. in 15 ml of ethyl acetate was added dropwise to the filtrate and the residue was dried over sodium sulfate and concentrated in vacuo. To give 4- (6-nitropyridin-3-yl) piperazin-2-one as pale yellow solid MS m / z 223.2 (M + 1).

Step z: To a round-bottomed flask is (6-nitropyridin-3-yl) piperazin-2-one 141-3 added 4-88 ΕΡ240383261 ΕΡ240383261 et al. The reaction was stirred for 4 hours under hydrogen atmosphere by the addition of a hydrogen flask. The solid reaction was removed by filtration, the solvent was removed by rotary evaporation to give To give 4- (6-aminopyridin-3-yl) pyrazin-2-one 141-4 as a purple solid MS m / z 193.2 (M + 1)

Step 3: To a mixture of 2- (4- (2-methylpyridin-4-yl) phenyl) acetic acid 26-3 (22 mg, 0.1 mmol), 4- (6-aminopyridin-3-yl ) piperazine-2-one 141-4 (19 mg, 0.1 mmol) and O- (7-azabenzotriazol-1-yl) -N, N ', N'-tetramethyluronium hexaflurophosphate (HATU) (40 mg , 0.1 mmol) in DMF (1 mL) was added DIEA (52 mL, 0.3 mmol) at ambient temperature. The mixture was stirred for 3 d. The reaction mixture is diluted in DMSO and purified by reverse phase HPLC to afford 2- (4- (2-methylpyridi-4-yl) phenyl) -N- (5- (3-oxopiperazin-1-yl) pyridin-2-yl) acetamide 141. MS m / z 402.2 (M + 1). 1 H NMR: 400MHz (DMSO-d6) δ 10.53 (s, 1H), 8.49 (d, 1H), 8.05-8.01 (m, 2H), 7.94 ( d, 1H), 7.75 (d, 2H), 7.57 (s, 1 H) 7.48-7.48 (m, 3H), 7.41 (dd, 1H), 3.74 (s, 1H), 3.71 (s 2H) δ 2.54-2.50 (m, 7H), 1.24 (s, 2H).

Example 21 N- (5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide (143)

Step 1 reacts with a sealed tube loaded with b-iodopyridin-

2-araine-143-1 (1.1 g, 5 mmol), (0.61 g, 7.4 mmol), Cul (0.31 g, g, 10 mmol) was added DMF 4- The reaction mixture was stirred at room temperature for 30 minutes and the reaction mixture was allowed to warm to room temperature, The reaction was ethyl and the salt was removed by filtration. The filtrate was dried and the residue purified by flash chromatography on silica gel to give the eluted soln. with 10% methanol in ethyl acetate (4-methyl-1H-imidazol-1-yl) pyridin-2-amine 143-3 pearl white, MS m / z 175.2 (M + 1).

Step 2: To a mixture of 2- (4- (2-methylpyridin-4-yl) phenyl) acetic acid 26-3 (22 mg, 0.1 mmol), 5- (4-methyl-1H-imidazole yl) pyridine-2-amine 143-3 (18 mg, 0.1 mmol) and o- (7-azabenzotriazol-1-yl) -N, 12, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (40 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (52 mL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DMSO and purified by reverse phase HPLC medium to give N- (5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl) -2- (DMSO-d6) δ 10.91 (s, 1H), 4.00 (s, 1H) 1H), 8.58 (dd, 1H), 8.43 (d, J), 8.10 (m, 2H), 7.99 (m, 1H), 7.77 (d, 2H), 7.51 (s, 1H), 7.43-7.10 (m, 4H), 3.75 (s, 2H), 2.46 (s, 3H), 2.10 (s, 3H) H) . Example 22 2- (2 ', 3-dimethyl-2,4' -bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (145) 100 ΕΡ2403832Β1 'Ϊ & & \ \ \ \............................................................................... :, Τζ Τζ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ ΠΟ Τζ ΠΟ ΠΟ ΠΟ Τζ Τζ Τζ Τζ. "0Η cr-f

. 1 \ .J

c Υγ # ·! (I.e.

• VNV

J ΐγίζΐ ^ -, ρ stm

UjY

Step 1: To a flask seal was added 5- (4,4,5,5-tetramethyl-1,3,2-dioxaboroan-2-yl) pyridin-2-amine 145-1 (1.54 g, 7 mmol ) (500 mg, 0.7 mmol), toluene (50 mL), ethanol (12 mL) and 2M Na 2 CO 3 (11 mL) ). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90 ° C for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with 1 M aqueous HCl solution (50 ml). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting solution was evaporated and the remaining solid was extracted with ethyl acetate (100 ml x 3). The combined organic phases were concentrated to give 5- (pyridazin-3-yl) pyrid-2-amine 145-3 as a light brown foam. Step 2: A solution of 2- (6-chloro-5-methylpyrid-3-yl) acetic acid 86-7 (241 mg, 1.3 mmol ), 5- (pyridazin-3-yl) pyrimidin-2-amine 145-3 (224 mg, 1.3101 e24038321 mmol), 1,3-dicyclohexylcarbodiimide (325 mg, 1.6 mmol) and 4- (26 mg, 0.26 mmol) in DMF (6 ml) was stirred at room temperature for 10 hours The reaction mixture was filtered to remove the solid and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and concentrated to dryness by rotary evaporation.The crude product was purified by flash chromatography on silica gel, eluted with 5% methanol in dichloromethane to give 2- (6- 3-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide 145-4 as pale yellow solid MS m / z 340.2 (M + 1)

Step 3: To a reaction tube containing 2- (6-chloro-5-methoxypyridin-3-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl ) acetamide 145-4 (68 mg, 0.2 mmol), 2-methyl-4-16 mg, 0.2 mmol) and Pd (PPh3) 4 (DMF (0.9 ml) was added. The product was purified by HPLC - (2 ', 3-dimethyl-2,4apos; -bipyrimid-9- (tributylstanyl) pyridine (mg, 0.02 mmol) under argon. The reaction mixture was stirred at room temperature for 1 hour and then cooled to -78 ° C. The mixture was stirred at rt, (DMSO-d6) δ1.1.14 (s, 1H), 99.99 (d, 1H), 9.3 (s, 1H). (D, 1H), 8.49 (1H), 8.29 (dd, 1H), 8.45 (d, 1H) , 8.13 (d, 1H), 1.81 (dd, 1H), 7.73 (d, , 2.53 (s, 3H), 2.35 (s, 3H), 5.45

Example 23 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) acetamide (148) 102 ΕΡ2403832Β1

Step 1: To a mixture of 2- (6-Chloro-5-methylpyridin-3-yl) acetic acid 74-4 (100 mg, 0.54 mmol), 1 - [(6-aminopyridin-3- yl) piperazin-1-yl) ethanone 111-4 (140 mg, 0.64 mmol) and 0- (7-azabenzotriazole-1-yl) -N, N, γ ', ω-tetramethyluronium hexafluorophosphate (HATU) (220 mg, 0.58 mmol) in DMF (2 mL) was added DIEA (280 mL, 1.62 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO 3, then brine, dried over K 2 CO 3. The solvent was removed by rotary evaporation to give N- (5- (4-acetylpiperazin-1-yl) pyridine -2-yl) -2- (6-chloro-5-methylpyridin-3-yl) acetamide 148-1 (210 mg, 100%). MS m / z 388.1 (M + 1).

Step 2: The mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (6-chloro-5-methylpyridin-3-yl) acetamide 148-1 (80 mg, 0.21 mmol) and 2-methyl-4-

(1,1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (30 mg, 0.18 mmol) was added in DMF (1.5 mL) ). The reaction was stirred 103 ΕΡ2403832Β1

at 110 ° C for 20 hours. After cooling to room temperature, the reaction mixture was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2 ', Dimethyl-2,4'-bipyridin-5-yl) acetamide as white bead solid. MS m / z 445.2 (M + 1); 1 H NMR (DMSO-d 6) δ 10.57 (s, 1H), co OD (d, 1H), 8.40 (d, 1H), 7.98 (d, , 7.64 (d, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 2H), 3.70 (s, 2H), 3.50 (b, 4H), 3.09 (t, 2H), 2.49 (s, 3H), 2.28 (s, 3H), 1.97 (s, 3H).

Example 24 2-Ethyl-4- (3-methyl-5- (2-oxo-2- (5- (pyrazin-2-yl) pyridin-2-yl) ethenyl) pyridin-2-yl) pyridine 1-oxide (156) The 'oo /' Ά COOt!

Dbf 'mu

COPM XS-1

THE

w · ········································································································ • S, T π Ί ./'Vx ν / · ν, / S * '&quot; The invention relates to a process for the preparation of a compound of the formula: ## STR1 ## wherein X is as defined in formula (I). occ omp

To a flask were added 5-bromo-2-chloro-3-methylpyridine 156-1 (4.13 g, 20 mmol), Cul (380 mg, 2.00 mmol), Cs2CO3 (18 g, 60 mmol ), 2-picolinic acid (480 mg, 4.0 mmol). The flask was evacuated and filled again with argon 3 times. Anhydrous dioxane (40 ml) was added to the flask, followed by diethyl malonate 156-2 (6 ml, irunol). The mixture was cooled to 96øC for 36 hours under argon. After being cooled to room temperature, the mixture was partitioned between ethyl acetate and water. The organic portion was dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash chromatography, eluted with 20% ethyl acetate in hexanes to give diethyl 2- (6-chloro-5-methylpyridin-3-yl) malonate as a colorless oil. MS m / z 286.1 (M + 1).

Step 2: To a reaction flask containing diethyl 2- (6-chloro-5-methylpyridin-3-yl) malonate 156-3 (1.00 g, 4.00 mmol), 2-methyl-4- (tributylstanil ) pyridine (1.53 g, 4.00 mmol) and Pd (PPh 3) 4 (440 mg, 0.4 mmol) under argon was -Or. DMF (20 ml) was added. The mixture was stirred at 120 ° C for 10 hours. After the mixture was cooled to room temperature, the 1N aqueous KF solution was added thereto and stirred for 15 minutes. The mixture was diluted with ethyl acetate and the two layers were separated. The organic layer was further washed with water and brine, dried over Na 2 SO 4, concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel. silica gel, eluted with 5% methanol in dichloromethane to give diethyl 2- (2 ', 3-dimethyl-2,4-bipyridin-5-yl) malonate as crude oil MS m / z 343.1 ( M 4 · 1)

Step 3: A mixture of diethyl 2- (2 ', 3'-dimethyl-2,4'-oxyimino-5-yl) malonate 156-4 (935 mg, 3 min.)) And NaOH (480 mg , 12 mmol) in THF (1.8 ml) and water (1.8 ml) f

50 to 65 ° C for 3 hours. After being cooled to room temperature, the mixture was treated with 3N aqueous HCl solution to adjust the pH to around 3, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted. With 20 105 Ų 2403832 æl of methanol in ethyl acetate. The organic extract was concentrated to give 2- (2 ', 3-dimethyl-2,4'-bipyridin-5-yl) acetic acid as white solid. MS m / z 243.1 (M + D +

Step 4: To a solution of 2- (2 ', 3-dimethyl-2,41-bipyridin-5-yl) acetic acid 156-5 (100 mg, 0.41 mmol) in dichloromethane (3 mL) and methanol ( 0.5 ml) was added mCPBA (91 mg, 0.41 mmol) in small portions at 0 ° C. The mixture was stirred for 3 hours at 0 ° C, and then concentrated to dryness to give 4- (5- (carboxymethyl) -3-methylpyridin-2-yl) -2-methylpyridine-1-oxide as 6-6 white solid, which was used for the next step without further purification. MS m / z 259.1 (M + 1).

Step 5: A mixture of 4- (5- (carboxymethyl) -3-methylpyridin-2-yl) -2-methylpyridine 156-6 from Step 4 (0.41 mmol), 5- (pyrazin-2 (141 mg, 0.82 mmol), 1,3-dicyclohexylcarbodiimide (188 mg, 0.90 mmol) and 4- (dimethylamino) pyridine (16 mg, 0.16 mmol ) in DMF (2 ml) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble material and the filtrate was purified by reverse phase HPLC to give 2-methyl-4- (3-methyl-5- (2-oxo-2- - (pyrazin-2-yl) pyridin-2-ylamino) ethyl) pyridin-2-yl) pyridine as white solid. MS m / Z 413 (Z + 1); ] 1 H NMR 400 MHz (DMSO-d 6) δ 11.1. . (d, 1H), 8.72 (m, 1H), 8.62 (d, 1H), 9.5 (dd, 1H) , 8.48 (d, 1H), 8.31 (d, 1H), 8.21 [(1H, 1H) (m, 2H), 7.52 (dd, 1H), 3.86 (s, 2H) 41 (s, 3H), 2.40 (s, 3H). 106 ΕΡ2403832Β1

EXAMPLE 2 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methyl-4- (2-fluoropyridin-4-yl) phenyl) acetamide (159)

Compound 159

Step 1: To a mixture of 2- (4-bromo-3-methylphenyl) acetic acid 24-5 (100 mg, 0.44 mmol), 1- (4- (6-aminopyridin-3-yl) piperazin-1 -yl) ethanone 111-4 (96 mg,

0.44 mmol) and HATU (200 mg, 0.53 mmol) in DMF (2 mL) was added DIEA (230 μL, 1.32 mmol) and the mixture was stirred at room temperature. during the night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2 SO4 &gt; 4 and the solvent was evaporated. The residue was flash chromatographed on silica gel to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-bromo-3-methylphenyl) acetamide 159-1. MS m / z 431.1 (M + 1).

Step 2: To the mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-bromo-3-methylphenyl) acetamide 159-1 (65 mg, 0.15 mmol) ) and 2-methyl-4- (tributylstanyl) pyridine 159-2 (58 mg, 0.15 mmol) in DMF (0.8 ml) was added [1,1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (30 mg, 0.036 mmol). The reaction was stirred at 110 ° C for 20 hours. After cooling to room temperature, the reaction mixture was diluted in DMSO and purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methyl-4- (2-methylpyridin-4-yl) -phenyl) acetamide as white beaker, MS m / z 444.2 (M + 1); (D, 1H), 7.88 (d, 1H), 8.41 (d, 1H), 7.98 (d, 1H) (M, 2H), 7.16 (s, 1H), 7.1 2-7.09 (m, 2H), 7.1-7.7 3.61 (s, 2H), 3.52 (m, 4H), 3.08 (t, 2H), 3.02 (t, 2H), 2.1 / 97, 3 H).

Example 26 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-fluoro-4- (2-methylpyridin-4-yl) phenyl) acetamide (168)

Compound 168

Step 1: To a mixture of 2- (4-chloro-3-fluorophenyl) acetic acid (188 mg, 1.0 mmol), 1- (4- (6-aminopyrid-3-yl) (220 mg, 1.0 mmol) and HATU (400 æg, 1.05 mmol) in DMF (4 mL) was added DIEA (521 æL, 3.0 mmol ) and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na 2 SO 4 and the solvent was evaporated. The residue was flash chromatographed on silica gel to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-chloro-3-fluorophenyl) acetamide 168-2. MS m / z 391.1 (M + 1).

Step 2: To the mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-chloro-3-fluorophenyl) acetamide 168-2 • Λ (80 mg, 0.2 mmol) and 2-methyl-4- (tributylstanyl) pyridine (78 mg, 0.8 mmol) were added. (2 mmol) in DMF (0.6 ml) was added [1,1 (diphenylphosphino) ferrocene] dichloropalladium (II) (33 mg, mmol) The reaction was stirred at 110 ° C during cooling to room temperature The reaction was diluted in DMSO and purified by reverse phase HPLC to give N- (5- (4-acetylphenyl) pyrimidin-2-yl] -2- (3-fluoro- (M + D) + 1 H NMR (400 MHz, DMSO-d6): δ 0.90 (s, 3H) ) δ 10.57 (S, 150), 8.52 (d, 1H), 8.04 (S, 1 H), 7.93 (d, 1H), 7.59 (m, 1H) (B, 2H), 3.14 (bf 2H), 3.08 (b, 2H), 3.68 (s, 2H) 55 (S, 2H), 2.51 (s, 3H), 2.04 (s, 3H).

(4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) -3- (trifluoromethyl) phenyl) acetamide (172) -1

oo

To an acetylpiperazin-1-yl) pyridazin-2-yl) -2- (4-bromo-3- (trifluoromethyl) phenyl) acetamide 192-1 (300 mg, 0.62 mmol) 2-methylpyridin-4-ylboronic acid 172-1 (127 mg, 0.93 mmole) and F 'd (PPh 3) 4 (36 mg, 0.03 mmol) (6 ml), ethanol (2 ml) and saturated sodium carborate (2 ml) was added. The reaction mixture was sparged with nitrogen and heated to 110 ° C for 10 hours. After the reaction was cooled to room temperature, partitioned between ethyl acetate and saturated NaHCO 3 and the organic phase was washed with brine and dried over Na 2 SO 4. solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2 4-yl) -3- (trifluoromethyl) phenyl) acetamide 1 H NMR 400 MHz (DMSO-d 6):? 10.67 (s, 1H), 8.66 (d, 1H), 8.05 (m, 1H), 7.94 (m, 2H), 7.75 (d, 1H), 7.52 (s, 1H), 7.45 (m, 3H), 3.88 (s, 2H), 3.58 (b, 4H), 3.14 (b, 2H), 3.09 (b, 2H), Example 28 N- (5- (4- (Cyanomethyl) piperazin-1-yl) pyridin-2-yl) -2- (4-chlorophenyl) (2-methylpyridin-4-yl) phenyl) acetamide (175)

A mixture of 2- (4- (2-methylpyridin-4- (5- (piperazin-1-yl) pyridin-2-yl ) acetamide 131-1 mmol), 2-bromoacetonitrile (8 æL, 0.12 mmol) and

Stirred potassium carbonate the temperature was poured into water (5 ml, v / v). The Na 2 SO 4 phases are concentrated. (28 mg, 0.20 mmol) in DMF (1 ml) was stirred overnight. The crude product was purified by reverse phase to give N- (5- {4- (cyanomethyl) piperazin-1-yl) -1H-1 2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide 175. MS m / z 427.2 ( NMR (400 MHz, CDCl 3): δ 8.37 (d, 1H), 7.94 (s, 1H), 7.87 (d, 1H), 7.68 (d, 2H), (S, 1H), 7.48-7.44 (m, 3H), 7.36 (dd, 1H), 3.74 (s, 2H), 3.67 (s, 2H), 3.17 (t, 4H), 2.69 (t, 4H), 2.54 (s, 3H) 110 29 ΕΡ2403832Β1

Example 176 N- (5- (4-cyanopiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide (176)

Step 1: A mixture of 2- (4- (2-methylpyridin-4-yl) phenyl) -N- (5- (piperazin-1-yl) pyridin-2-yl) acetamide 131-1 (39 mg, , 10 mmol), cyanogen bromide (13 mg, 0.12 mmol) and Potassium carbonate (28 mg, 0.20 mmol) in DMF (1 ml) was stirred at ambient temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 ml x 3). The combined organic phases were dried over Na 2 SO 4, and concentrated. The crude product was purified by reverse phase HPLC to give N- (5- (4-cyanopiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) NMR (400MHz, CDCl 3) δ 8.39 (d, 1Hz), 7.96 (s, 1H), 7.96 (s, 1H). 7.89 (d, 1H), 7.68 (d, 2H), 7.58 (s, 1H), 7.50 (d, 1H), 7.46 (d, 1H), 3.74 (s, 2H), 3.35 (t, 4H), 3.18 (t, 4H), 2.55 (s, 3H).

Example N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-chloropyridin-4-yl) phenyl) acetamide (177) 111 ΕΡ2403832Β1

Compound 177

Step 1: To a mixture of 2- (4-iodophenyl) acetic acid 177-1 (524 mg, 2.0 mmol), 1- (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone 111-4 (440 mg, 2.0 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', Ν' -tetramethyluronium hexafluorophosphate (HATU) (788 mg, 2.1 mmol ) in DMF (10 mL) was added DIEA (1.04 mL, 6.0 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted in ethyl acetate, washed with saturated NaHCO 3, then brine, dried over Na 2 SO 4. The solvent was removed by rotary evaporation to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-iodophenyl) acetamide 177-2 as an ocher solid. MS m / z 4 65.2 (Μ + 1).

To a sealed tube was added N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-iodophenyl) acetamide 177-2 (100 mg, 0.22 mmol) 2-chloropyridin-4-ylboronic acid 177-3 (52 mg, 0.33 mmol), Pd (PPh3) 4 (23 mg, 0.02 mmol), saturated Na2 CO3 (1 mL), ethanol (1 mL ) and toluene (3 ml). The reaction was heated to 110 ° C and stirred for 16 hours. The reaction was cooled to room temperature, then extracted with ethyl acetate. The crude product was purified by flash chromatography on silica gel, eluted with ethyl acetate to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2- 4-yl) phenyl) acetamide as white bead solid. MS m / z 45 0.1 (M + 1); 1h and IMN 400 MH z (DMSO-d 6) δ 10.51 (s, 1H), 8.40 (d, 1H), 1 and '(d, 1H) &quot;? ΐ! (d, 1H), 7.19 (d, 2H), 7.69 (dd, 1H), 7.43 (d, 2H), 7.37 (dd, 1H), 3.68 (2H), 3.52 (m, 4H), 0.99 (t, 2H), 3.02 (E, 2H) 97 (s, 3H).

Example 31 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-fluoropyridin-4-yl) phenyl) acetamide (178)

To a sealed tube was added N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-iodophenyl) acetamide 177-2 (520 mg, 1.1 mmol), 2-fluoropyridin-4-ylboronic acid 178-1 (237 mg, 6 mmol), Pd (PPh 3) 4 (65 mg 0.055 branch 1) f N 3. r Γ) d Λ + - n / ; or Li. (5 ml), ethanol (5 ml) toluene (15 ml). The reaction was warmed to 170Â ° C and stirred. for 16 hours. The reaction was cooled to room temperature, and extracted with ethyl acetate. The crude product was purified by flash chromatography on silica gel, eluted with ethyl acetate to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2- -fluoropyridin-4-yl) phenyl) acetamide as white bead solid. MS m / z 433: (M + 1); : 1 H NMR 400 δ 1Hz (DMSO-d 6) δ1.58 / (d, 1H, J = 5.6 Hz), 8.44 (d, 1H, J = 2.8 Hz), 7.94 J = 9.2, N = 4. (M, 2H), 7.71-7.69 (m, 1H), 7.53-7.49 (m, 3H), 7.44 (dd, 1H, J1 = 9.2 Hz (S, 2H), 3.59 (b, 4H), 3.16 (t, 2H, C2-8), 3.09 (t, 2H) , 2H, J = 2.8Hz), 2.04 (s, 3H). 113 ΕΡ2403832Β1

Example 32 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide (181)

Step 1: A mixture of 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) acetic acid 111-10 (50 mg, 0.2 mmol), 5- (pyridazin-3-yl ) pyridin-2-amine 145-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4- (dimethylaminopyridine) (4 mg, 0.04 mmol) in DMF (0.9 ml) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble material and the filtrate was purified by reverse phase HPLC to give 2- (3-cyano-4- (2-methylpyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide as a white solid. MS m / z 4 (17.2 (M + 1); 1 H NMR 400 MHz (DMSO-? 5-6) δ 11 .1.3 (S, 1H), 9.22 (dd, 1H), : 9.13 (d, 1H), 8.59 (d, 1H), 8.56 (dd, 1H) , 7.98 (d, 1H); 7.83-7.79 (m, 2H); (d, 1H), 7.48 (s, 1H), 4.42 (dd, 1H), 5.95 (s, 2H), 2.56 (s, 3, 3H).

Example 33 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methoxy-4- (2-methylpyridin-4-yl) phenyl) acetamide (182) ΕΡ2403832Β1

Step v -fm n -, Ί 1: mg, room temperature. The solution of 2- (4-hydroxy-3-1) and TEA (404 mg, 4apos; -trifluoric acid (564 g) was heated to 180 ° C for 1 hour. ) was added to the mixture after addition and stirring.The mixture was partitioned between DCM and water.The organic phase was washed with brine and dried over Na2SO4. solvent was removed by rotary evaporation to give 2- (3-methoxy-4- (t-fluoromethylsulfonyloxy) phenyl) acetic acid 182-2 (590 mg, 95%).

Step 2: The mixture of 2- (3-methoxy-4- (trifluoromethylsulfonyloxy) phenyl) acetic acid 182-2 (590 mg, 1.9 mmol) and 2-methyl-4- (tributylstynyl) pyridine. (730 mg, 1.9 mmol) in DMF (2.0 mL) was added [1,1â € ²-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (33 mg, 0.04 mmol). The reaction was stirred at 110 ° C for 20 hours. After cooling to room temperature, the reaction mixture was diluted in DMSO and purified by reverse phase HPLC to give 2- (3-methoxy-4- (2-methyl-4-pyridin-4-yl) phenyl) acetic acid 182-3. MS m / z 258.1 (M + D.

Step 3: To a mixture of 2- (3-methoxy-4- (2-methylpyridin-4-yl) phenyl) acetic acid 182.3 (26 mg, 0.1 mmol), 1- (4- (6- (22 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (0.6 mL) was added diisopropylethylamine (52æL, 0.3 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted in DMSO and purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methoxy-4- 2-methylpyridin-4-yl) phenyl) acetamide 182. MS m / z 466 (M + 1). NMR (400 MHz, DMSO-d6, Î'10.51 (1H, d), 4.43 (d, 1H), 8.03 (s, 1H), 7.94 (d, 1H). 4 (s, 1H), 7.04 (d, 1H), 3.79 (s, 2H), 3.72 (m, 3H) 2H), 3.14 (b, 2H), 7.0 (b, 2H), 2.49 (3H, 3H), 2.04 (s, 3 H), 1.23 (s, 3H).

Example 34 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyridin-4-yl) phenyl) acetamide (183)

.................... vhi &gt; 4 v &lt; ϊ V · ..; / *** # -¾. ν ν »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »»

Step 1: To a sealed tube was added 5-bromo-2-iodopyrimidine 183-1 (114 mg, 0.4 mmol), 2-methyl-4- (4,4,5,5-tetramethyl- 2-dioxaborolan-2-yl) pyridine 183-2 (88 mg, 0.4 mmol), Pd (PPh 3) 4 (23 mg, 0.02 mmol), Na 2 CO 3 (170 mg, 1.6 mmol), toluene 0.4 ml), H 2 O (0.4 ml) and ethanol (0.1 ml). The reaction mixture was stirred at 100 ° C for 10 hours. After cooling to ambient temperature, the solvents were evaporated to dryness. and evaporated and the residue was redissolved in water (3 ml) and extracted &lt; was treated with 1 L acetate (5 ml x 3). The combined organic phases were dried over Na 2 SO 4, concentrated. The residue was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to give 5-bromo-2- (2-methylsulpyridin-4-yl) pyrimidine 183-3. MS m / z 25 0.0 (SM + 1).

Step 2: the one. (2-tert-butoxy-2-oxoethyl) zinc (II) chloride was added, followed by addition of 5-bromo-2- (2-methylpyrimidin- (0.25 mL, 0.30 mmol), Pd (dba) 2 (6 mg, 0.01 mmol), N-phos (14 mg, 0.02 mmol) and THF (1.5 mL). The reaction mixture λ2403832 foi1 was bubbled with nitrogen for 1 minute and stirred at 100 ° C for 1 hour. After cooling to room temperature, all solvent was evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel and eluted with 25% ethyl acetate in hexane to give tert-butyl 2- (2- (2-methylpyridin-4-yl) pyrimidin-5-yl) butyl ester 183-4. MS m / z 286.2 (M + 1).

Step 3: A mixture of tert-butyl 2- (2- (2-methylpyridin-4-yl) pyrimidin-5-yl) acetate 183-4 (35 mg, 0.12 mmol) and TFA (0.5 mL ) in DCM (3 ml) was stirred at room temperature for 2 hours. The crude product, 2- (2- (2-methylpyridin-4-yl) pyrimidin-5-yl) acetic acid, 183-5, was dissolved in DMF (2 ml). 1- (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone (35mg, 0.16mmol) and DIEA (107æl, 0.61mmol) were added to the solution before O -hexaflurophosphate - (7-azabenzotriazol-1-yl) -N, N, Ν ', N'-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC in methanol to afford N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2- (2- ylpyridin-4-yl) pyrimidin-5-yl) a &lt; 1 H NMR (CDCl 3) δ 8.47 (s, 2H), 8.50 (c, 1H), 8.22 (s, 1H) 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.38 (d, 1H), 3.83 (s, 2H), 3.68 (d, (t, 2H), 3.64 (t, 2H), 3.15 (t, 2H), 2.09 (t, 2H), 2.09 , 118 ΕΡ2403832Β1

Example 3b N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2-methyl-2,4'-bipyridin-5-yl) acetamide (184)

/ = N \ a αζ &quot; -γ ° γ; Pd (db) 2 / CT-G-Pt-C%-C%-H₂O-THF, 70øC; 1S4-1 se-s 184-S -Va / rl Τ'Ο W Pd (PPhj) 4 Cycle YV M 0 DME / HaO / EtOH 183-2 G 184

Step 1: To a sealed tube was added 5-bromo-2,3-dichloropyridine 184.1 (113 mg, 0.50 mmol), (2-tert-butoxy-2-oxoethyl) zinc (II) chloride (36 mg, 0.05 mmol) and THF (1: 1) to give the title compound as a white solid (0.25 g, 5 ml). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 70 ° C overnight. After cooling to room temperature, all solvent was evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to give tert-butyl 2- (5,6-dichloropyridin-3-yl) acetate 184-3. MS m / z 262.1 (M + 1). 119 ΕΡ2403832Β1

Step 2: A mixture of tert-butyl 2- (5,6-dichloropyridin-3-.11) acetate 184-3 (130 mg, 0.49 mmol) and TFA (0.5 mL) in DCM (3 mL ) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2- (5,6-dichloropyridin-3-yl) acetic acid 184-4, was dissolved in. DMF (3 mL). 1- (4- (6- (6-Amino-pyridin-3-yl) piperazin-1-yl) ethanone (12.1 mg, i.e. 5 mmol) and DIEA (435 μl, 2.5 mmol) were added to the solution before O- (7-azabenzotriazol-1-yl) -Î ±, Ν, N ', Ν'-tetramethyluronium hexafluorophosphate (277 mg, 0.73 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by flash chromatography on silica gel and eluted with 5% MeOH in CH 2 Cl 2 to give N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (5- 6-dichloropyridin-3-yl) acetamide 184-5. MS m / z 408.1 (M + 1).

To a sealed tube was added N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (5,6-dichloropyridin-3-yl) acetamide 184-5 (65 mg , 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 183-2 (42 mg,

(9 mg, 0.08 mmol), Na 2 CO 3 (84 mg, 0.79 mmol), H 2 O (0.5 mL) and ethanol ml). The reaction mixture was stirred at 100 ° C overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give crude N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2- (2-methylpyridin-4-yl) pyrimidine -5-yl) acetamide 184. MS m / z 4/5, (m + 1); 1 H NMR 400 MHz (MeOD) δ 8.52 (d, 2H), 8.46 (d, 1H), 7.98-7.95-7.49-7.46 (m, 1 Hz) 2H), 3.62 (t, 2H), 3H), 2.08 (s, 3H). 2H), 7.87 (d, 1H), 7.53 (s, 1H), 7.33 (dd, 1H), 3.81 (s, 2H), 3.67 (t, t, 2H), 3.08 (t, 2H), 2.56 (s, 120 ΕΡ2403832Β1

Example 36 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2-methyl-2,4'-bipyridin-5-yl) acetamide (188)

DMF / H20

ZnClN; Pd 2 (d-Q'Phos

To a sealed tube was added N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-chloro-2'-methyl-2,4 '-bipyridin-5- yl) acetamide 184 (46 mg, 0.10 mmol), zinc cyanide (14 mg, 0.12 mmol), Pd2 (dba) 3 (9 mg, ) and DMF / H 2 O (99/1, v / v), the reaction mixture was bubbled with nitrogen for 1 minute and stirred at 130 ° C overnight. After cooling to room temperature, the solvents were evaporated and the crude product was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-21- Δ '-β-pyridin-5-yl) acetamide 188. MS m / z 456.2 (M + 1): NMR 400 MH z (M +) .delta.0.0 (d, 1H), 8.56 (d, 1H) (D, 1H), 7.78 (s, 1H), 7.7-3.70 (m, 1 Hz), 7.98 (s, (T, 2H), 3.16 (t, 2H), 3.69 (t, 2H), 3.65 (t, 2H) 11 (t, 2 H), 2.61 (s, 3H), 2.09 (s, 3H),

Example 37 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl-3- (trifluoromethyl) -2,4'-bipyridin-5-yl) acetamide ( 189) 121 ΕΡ2403832Β1F, c

Pd (ti &amp; a) 2 / CT-Q-PFGs THF. 100CC. Ihr F

Pt <PPh3) VNa2C03 Tci / H20 / EtOH 100 ° C, o / rt

18Ϊ-4 TFA CH2Cl ·

188 * 5

To a sealed tube was added 5-bromo-2-chloro-3- (trifluoromethyl) pyridine 189-1 (170 mg, 0.65 mmol), (2-tert-butoxy-2-oxoethyl) zinc chloride (19 mg, 0.03 mmol), Pd (dba) 2 (19 mg, 0.03 mmol), potassium carbonate (46 mg, The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100 ° C for 1 hour. After cooling to room temperature, all solvent was evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to give tert -butyl 2- (6-chloro-5 '- (trifluoromethyl) pyridin-5-yl) acetate butyl ester 189-3, MS m / z 296.1 (M + 1).

Step 2: To a sealed tube tert-butyl 2- (6-chloro-5- (trifluoromethyl) pyridin-3-yl) acetate 189-3 (318 mg, 1.08 mmol), 2-methyl-4 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (283 mg, 1.29 mmol), Pd (PPh3) 4 (62 mg, 0.05 mmol), Na2 CO3 (342 mg, 3.22 122 ΕΡ240383261

mmol), toluene (3 ml), H 2 O (3 ml) and ethanol (0.55 ml). The reaction mixture was stirred at 100 ° C overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (10 ml) and extracted with ethyl acetate (10 ml x 3)

The combined extracts were washed with EtOAc and eluted with ethyl acetate in hexane to give 2- (2'-methyl-3- (trifluoromethyl) -2,4'-bipyridin-5-yl) acetate tert-butyl 189-4. MS m / z 35.2 (M + 1).

Step 3: To a mixture of tert-butyl 2- (2'-methyl-3- (trifluoromethyl) -2,4'-bipyridin-S-yl) acetate 189-4 (230 mg, 0.65 mmol) and TFA (1 ml) in DMF (5 ml) was stirred at room temperature for 5 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2- (2'-methyl-3- (trifluoromethyl) -2,4'-bipyridin-5-yl) acetic acid 189-5, was dissolved in DMF (4 mL). 1- (4- (6-amino-pyridin-3-yl) piperazin-1-yl) ethanone (173 mg, 0.78 mmol) and DIEA (910 μL, 5.22 mmol) were added to the solution before O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (372 mg, 0.98 mmol). The mixture was stirred at room temperature overnight.

The solvent was removed by rotary evaporation. The crude product was purified by HPLC reverse phase HPLC to give N- (Î ± - (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl L-3- (trifluoromethyl) -2,4'-bipyrimidin-5-yl) ac eamide 189. MS m / e; 499.2 (M + 1); ) δ NMR 400 MHz (MeOD) δ 8.78 (s, 1H), 8.48 (d, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.88 (d, 1H), 7.49-7.36 (m, 2H), 7.13 (d, 1H), 3.92 (s, 2H), 3.69 (t, 2H), (S, 3H), 3.16 (t, 2H), 3.11 (t, 2H), 2.57 (s, 3H) 123 ΕΡ240383261

Example 38 ΕΡ240383261 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-

Step 1: To a sealed tube were added 5-bromo-2-chloro-3-fluoropyridine 190-1 (210 mg, 1.0 mmol), 86-5 chloride in ether ether), reaction Q-phos was added at 100øC at room temperature the residue was 0.5 M (2-tert-butoxy-2-oxoethyl) zinc (II) (2.4 mL, 1.2 mmol), Pd (dba) 2 (29 mg, The mixture was bubbled with nitrogen for 1 minute and stirred for 1 hour. After cooling to room temperature, all solvent was evaporated and redissolved in ethyl acetate, washed The crude product was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to afford 2- (6-methoxyphenyl) chloro-5-fluoropyridin-3-yl) acetate 190-3 MS m / z 246.1 (M + 1).

Stage

A mixture of tert -butyl 2- (6-chloro-Î ± -fluoropyridin-3β- (2β) -phenyl) acetate 190-3 (123 mg, 0.50 mmol) and TFA (0.5 mL) in DMF ml) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2- (6-chloro-5-fluoropyridin-3-yl) acetic acid, 190-4, was dissolved in DMF (3 ml). 1- (4- (6-aminopyridin-3-yl) piperazin-1-yl) etanone (110 mg, 0.50 mmol) and Dlα (500 μl, 2.87 mmol) were added to the solution before O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by flash chromatography on silica gel and eluted with 5% MeOH in CH 2 Cl 2 to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (6-chloro -5-fluoropyridin-3-yl) acetamide 190-5. MS m / z 392.2 (Μ + 1).

To a sealed tube were added N - (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (6-chloro-5-fluoropyridin-3-yl) acetamide 190-5 (59 mg, 0.15 mmol), 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl) pyridine 183-2 (49 mg, Pd (PPh 3 mm or 1), ba2 CO3 (7.9 mg, 0.75 mmol), Toluene (0 ml) and ethanol (0.2 ml). The reaction mixture at 100 ° C overnight. After cooling to medium, the solvents were removed and evaporated. The crude product was; HPLC from reverse phase to acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-fluoro-2,4,5-bipyridyl) -yl) acetamide 190. MS m / z (M, 2H), 7.87 (d, 1H), 7.81 (s, 1H), 7.75-7.69 (m, 2 1H), 3.84 (s, 2H), 3.67 (t, 2H), 3.62 (t, 2H), 3.08 (t, 2H)> 2.56 (s, 3H), 2.08 (s, 3H), G 08 medium-methyl: 125 ΕΡ2403832Β1

Example 39 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (2-fluoro-5-methyl-4- (2-methylpyridin-4-yl) phenyl) acetamide (191 )

pyrrolidone with 4 g, 10 mmol), &quot; -7.0 g /

Step 1: To a 2-fluorophenyl-2-fluoro-5-methylphenyl 191-1 (2.04 g, 2-methylpyridin-4-ylboronic acid, 191- 2 (1.37 g, and Pd (PPh 3) 4 (0.4 g, 0.3 mmol) was added toluene (30 mL), ethanol (10 mL) and saturated sodium carbonate (10 mL) After the reaction was cooled, the reaction mixture was partitioned between ethyl acetate and saturated NaHCO 3, and the residue was partitioned between ethyl acetate and saturated NaHCO 3,

(CDCl3) δ (CDCl3):? the solvent was removed by means of δ-τ-τ-λ-1. And the residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexane to give 2-fluoro-5- methyl-4- (2-methylpyridin-4-yl) phenyl] -amide. MS m / z 217.1 (M + 1). in ; (1.02 rite

Step 2: methylpyridin-4 (16 ml) was added aniline 191-3 added with N, N-dimethylaminopropylamine (0.9 mmol) in CH2 Cl2 of isoamyl ( After the reaction was heated at 100 DEG C. The solvent was removed by rotary evaporation and the residue was dissolved in ethyl acetate and washed with Na2 S205 , brine and brought to dryness by rotary evaporation.

purified by means of C O OITI3. Flash chromatography on silica gel, eluted with 40% ethyl acetate / hexane to give 4- (5-fluoro-4-iodo-2-methylphenyl) -2-methylpyridine 191-4, MS m / z 328.10 (M + 1).

Step 3: To a sealed tube charged with 4- (5-fluoro-4-iodo-2-methylphenyl) -2-methylpyridine 191-4 (200 mg, 0.6 mmol), Pd2 (dba) 3 (28 mg, 0.03 mmol), and Q-Phos (21 mg, 0.03 mmol) was added anhydrous THE (2.5 mL). The reaction vessel was flushed with nitrogen and 0.5 M (2-tert-butoxy-2-oxoethyl) zinc (II) chloride in ether, 1.34 mL, 0.67 mmol) was added subsequently. The reaction was heated to 70 ° C for 12 hours. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography on silica gel, eluted with 50% ethyl acetate in hexane to give 2- (2-fluoro-5-methyl-4- (2- methyl-pyridin-4-yl) -phenyl) acetate 191-5. MS m / z 316.10 (M + 1).

A solution of 2- (2-fluoro-5-methyl-4- (2-methylpyridin-4-yl) phenyl) acetate diethyl tert -butyl, 5 (80 mg, 0.37 mmol) was added dropwise over a period of 1 hour. The TFA, A (2 m 1) was added. The reaction was stirred at room temperature for 2 hours. Solvent and TFA was removed by rotary evaporation to give 2- (2-fluoro-5-methyl-4- (2-methylpyridin-4-yl) phenyl (191) 6. The powder was used for the next step without further purification.

Step 5: To a mixture of 2- (2-fluoro-5-methyl-4- (2-methylpyridin-4-yl) phenyl) acetic acid 191-6 (35 mg, 0.13 127 ÅΡ2403832 Β1 mmol) (30 mg, 0.13 mmol) and HATU (50 mg, 0.13 mm or 1 mmol) were added to a solution of 4- (6-aminopyridin-3-yl) ) in. DMF (1.0 mL), m.p. DIEA (67æl, 0.4mm or 1) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted in DMSO and purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2-fluoro-5- 1-methyl-4- (2-methylphenyl) in-4-yl) phenyl) acetamide 191. MS m / z Δ 62 O: m + 1). U: [NMR (400MHz, DMSO-d6) δ 10.51 (s, 1H), Î'49 (d, 1H), 8.03 (s, 1H); 91 (d, 1H), 7.43 (m, 1H), H! 1H), 7.28 (s, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 3.76 (s, 2H), 3.53 (s, 3H), 2.04 (s, 3H), 2.07 (b, 2H), 2.05 (b, 2H) 3H).

Example 40 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyrimidin-4-yl) -3- (trifluoromethyl) phenyl) acetamide (192)

Step 1: To a mixture of 2- (4-bromo-3- (trifluoromethyl) phenyl) acetic acid 46-6 (644 mg, 2.0 mmol), 1- (4- (6-aminopyridin-3 -yl) piperazin-1-yl) ethanone 111-4 (440 128 ÅΡ2403832Β1 ΕΡ2403832Β1 mg, 2.0 mmol) and HATU (798 DIEA added (1.04 mL) at room temperature was partitioned between organic phase solvent was evaporated, flash chromatography in mg, 2.1 mmol) in DMF (6 mL) was 6.0 mmol) and the mixture was stirred: overnight. The reaction mixture between ethyl acetate and water. and the residue was subjected to silica gel to give N- (5- (4-acetylpiperazin-1- (trifluoromethyl) phenyl) acet) m / z 485.1 (M + 1).

yl) pyridin-2-yl) -2- (4-bromo-3-mide 192-1 (920 mg, 95%). MS A solution of N- (5- (4-acetylpiperazin- ) pyridin-2-yl) -2- (4-bromo-3- (trifluoromethyl) phendyl) acetamide 192-1,4,4,4 ', 4', 5,5,5 ' , 5 ', 192-2 (0.51 g, 2 (dppf) 2 CH 2 Cl 2 (82) azido- (0.8 g, 1 mmol), 3,2-dioxaborolane), 3 mmol) PdCl 2 DMSO (5 mL) was cooled to 0 ° C for 2 hours. and the residue was partitioned between ethyl acetate and water, and the organic phase was dried, dried (Na 2 SO 4) and evaporated and flash chromatographed on silica gel to give N- (5- (4-acetylpiperazin- 1-yl) pyridin-2-yl) -2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (trifluoromethyl) phenyl) acetamide MS: m / z 533.2 (M + 1).

Step 3: A mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) -3- (trifluoromethyl) phenyl) acetamide 192-3 (53 mg, 0.1 mmol), 4-chloro-2-methylpyrimidine 192-4 (18 mg, 4 (11 mg, 0.01 mmol) and K 3 PO 4 (42 mg, 0.2 mmol) in dioxane (1.0 mL) was bubbled with CH2Cl2 and heated to 100 ° C for 2 hours. The salt was removed by filtration and the filtrate was brought to dryness by rotary evaporation. The residue was purified by HPLC reverse phase to give N - (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2-methylpyrimidin-4-yl) -3- (trifluoromethyl) phenyl) acetamide 192. MS m / z 499.2 (M + 1). NMR 400 MHz (DMSO-d6) δ 10.58 (s, 1H), 8.77 (d, 1H), 8.02 (s, 1H), 7.89 (m, 2H), 7.73 , 1H), 7.54 (d, 1H) Ί f &gt; 3.16 (s, 2H), 3.66 (b, 4H), 3.14 (b, 2H), 3.07 (b, 2H), 2.64 (s, 3H), 2.03 (s, 3H).

Example 41 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl) acetamide (193)

Compound 193 2-1 mmol), mg, 1.5 mg, 0.1 The reaction

To a reaction vial was added (6-Chloro-5-methylpyridin-3-yl) acetic acid 74-4 (185 mg, 2-fluoropyridin-4-ylboronic acid 193-1 (220 mmol), Pd (OAc ) 2 (12 mg, 0.05 mmol), S-Phos (41 mmol) and K 3 PO 4 (636 mg, 3 mmol) in 1 ml 2-butanol was treated at 100øC and stirred for 2 hours. cooled to room temperature and then diluted to DMSO The reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (η 2 240 38 32) (1) acid 1). To a reaction vial was added 2- (2'-fluoro-3-methyl-2,4f-bipyridin-5-yl) acetic acid 193-2 (60 mg, 0.17 mmol), 1- (4 - (6-aminopyridin-3-yl) piperazin-1-yl) ethanone 111-4 (50 mg, 0.22 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ' N-tetramethyluronium hexafluorophosphate (HATU) (115 mg, 0.3 mmol) and DIEA (104 mL, 0.58 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was diluted with DMSO and then purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-3- (2'-fluoro-3-methyl-2,4-bipyridin-5-yl) acetic acid as a white solid.

(Methyl methyl-2, 4'-bipyridin-5-yl) acetamide as white solid. NMR (400MHz, CDCl3): δ 7.88 (d, 1H), 7.42 (d, 1H) , J = 1.6 Hz), 8.28 (d, 1 w X.XX, J = 5.2 Hz), 7.98 (d, 1H, J = 2.8 Hz), 7.97 (d, 1-H, J = 9.2 Hz), 7.91 (d, 1H, J = 1.6 Hz), 7.50-7.48 (m, 1H), 7.37 ( dd, 1H, J 1 = 9.2: Hz, J 2 = 3, R 2 Hz), 7.30 (s, 1H), 3.1 (s, 2H), 3.5 (b, 4H), 3.09 (t, 2H, J = 5.2 Hz), 3.02 (t, 2H, U = b, z Hz), 2.30 (s, 3H), 1.97 (s, 3H) .

Example 42 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (2,3-difluoro-2,4'-bipyridin-5-yl) acetamide (194) F cvS or f-. The reaction was carried out in the presence of an acetylpiperazin-1-yl) pyridin-2-

Compound 194 was added N- (5- (4-yl) -2- (6-chloro-5-methyl-1H-indazol-

fluoropyridin-3-yl) acetamide 190-6 (66æg, 0.11 mole D 1, 2-fluoropyridin-4-yl) benzoic acid 193-1 (35 mg, (10 mg, 0.51 mmol), Pd (OAc) 2 (2 mg, 0.009 ml no 1), S-Phosphate (7 mg, 0.01 mmol) and K 3 PO 4 (108 mg, 0.51 mmol) 2-butanol (0.3 ml) The reaction was warmed to 100 ° C and stirred 2 hr. The reaction was cooled to room temperature and then diluted to DMSO. the filtrate was purified by reverse phase HPLC to afford N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2 ', 3-difluoro-2,4'- bipyridin-5-yl) acetamide 194 MS MS m / z 453.1 (Mel).

Example 43 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (5-fluoropyrimidin-4-yl) phenyl) acetamide (196)

Step 1: A mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-iodophenyl) acetamide 177-2 (398 mg, 0.86 mmol), 4- , 4,4,5,5-dioxaborolane) 192-2 (380 mg mmol) PdClz (dppf) 2 · CHCl3; (7 ml) was flushed with nitrogen for hours. A solution of 3.0 g of ethyl acetate and water. brine, or dried in 1: 1 to 2: 4

ϊ ς ς ς ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ DMSO (5) heated to 90 ° C for 2 hours in dichloromethane. The organic layer was washed with solvent and evaporated to dryness (4,4,5, residue was dissolved in dichloromethane). Flash chromatography on silica gel gave N - (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-secramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetamide

196-1. MS m / z 465.2 (M +).

Step 2: A mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (4,4,5,5-tetramethyl- 2-yl) phenyl) acetamide 196-1 (30 mg, 0.065 mmol), 4-chloro-5-fluoropyrimidine 196-2 (28 mg, 0.21 mmol) , 1.0 mmol) and K 3 PO 4 (90 mg, 0.424 mmol) in dioxane (0.6 mL) was sparged with nitrogen and heated to 110øC for 2 hours. The salt was removed by filtration and the filtrate was brought to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (5-fluoropyrimidin-4-yl) ) phenyl) acetamide 196. 1 H NMR (DMSO-d6) δ 10.54 (s, 1H), 9.06 (d, 1H), 8.90 (d, 1H) d, 1H), 7.98 (m, 3H), 7.86 (d, 1H), 7.49 (d, 2H), 7.37 (m, 1H), 3.73 (s, 2n) (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H).

Example 44 (±) - (5- (4-Chloropyrazin-1-yl) pyridin-2-yl) -2- (2'-ethyl- (methylsulfonyl) -2,4'-bipyridin-5-yl) acetamide (197) 133 ΕΡ2403832Β1

NaNCtyNaSMe - *

187-2

jjjCPBA

Br CH%

Yes, I, I7-3 + CJZrf

Or ° T &lt;

HF 8S-5

Pdid & aljCT Q Phos

TFA CH₂Cl₂ +

OH O / - \ / = N / \ / H ^ \ hatk / bsea / dmf

1S-7

r

Pd (PPI3) 4 Na2 CO3 To1 / H2 O / EtOH-V-o. // &quot; &quot; (

N-quot; and quot; 103-2

Step 1: 5-bromo-2-chloro-3- (methylsulfonyl) pyridine 197-3 was synthesized according to the literature procedure from 5-bromo-2-chloropyridin-3-amine 197-

Step 2: To a sealed tube was added b-bromo-2-C10-15-3- (methylsulfonyl) pyridine 197-3 (60 mg, 0.2 mmol) (2-tert- (0.54 ml, 0.27 mmol), P d (dbc) δ (6.4 mg, 0.7 mmol) 0.001 mmole 1), β-phole (16 mg, 0.02 mmol) and THF (v / ml). The reaction mixture was bubbled with nitrogen for 1 minute or stirred at 100 ° C for 1 hour. After cooling to 3, the solvent was collected, all solvent evaporated. evaporated and the residue was redissolved in ethyl acetate, washed with brine and dried over magnesium sulfate to give 2-tert-butoxide and brine, dried over Na2SO4 and concentrated by evaporation rotating. The product purified by flash chromatography eluting with 20% ethyl acetate in hexane (6-chloro-5- (methylsulfonyl) pyridin-3-yl) acetate butyl 197-5. MS m / z 306.1 (M + 1)

Step 3: A mixture of tert-butyl 2- (6-chloro-5- (methylsulfonyl) pyridin-3-yl) acetate 197-5 (40 mg, 0.13 mmol) and TFA (0.5 mL) in DCM (3 ml) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2- (6-chloro-5- (methylsulfonyl) pyridin-3-yl) acetic acid 197-6, was dissolved in DMF (2 ml). 1- (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone (35 mg, 0.16 mmol) and DIEA (114 μL, 0.65 mmol) were added to the solution before hexafluorophosphate of 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (75 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by flash chromatography on silica gel and eluted with 5% MeOH in CH 2 Cl 2 to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (6- chloro-5- (methylsulfonyl) pyridin-3-yl) acetamide 197-7. MS m / z 452.1 (M + 1).

To a sealed tube was added N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (6-chloro-5- (thiethylsulfonyl) pyridin-3-yl) acetamide 197-7 (30 mg, 0.07 mmol), 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 183-2 (22 mg (4 mg, 0.03 mmol), Na2 CO3 (22 mg, 0.20 mmol), Toluene (0.4 ml), H2 O (0.4 ml) and Pd (PPh3) ethanol (0.1 ml). The reaction mixture was stirred at 100 ° C overnight. After cooling to room temperature, the solvents were removed by means of rotary evaporation. The crude product was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-methyl-3- (methylsulfonyl) - (4'-bipyrimidin-5-yl) ac amide 197. 1 H NMR (MeOD) δ 8.81 (d, 1H), 8.52 (d, 1 H), 1.85 (m, , &lt; / RTI &gt; (d, 1H), 7.97 (s, 1H). 8 (d, 1H); (S, 1H), 7.37 (dd, 1H), 3.9 (s, 2H), 3.86 (t, 2H) 1 H-NMR (DMSO-d 6, 300 MHz): δ (t, 2H), 3.15 (t, 2H), 3.15 (t, 2H) H), 2.09 (s, 3H).

Example 45 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (6-methylpyrimidin-4-yl) phenyl) acetamide (198)

A mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) phenyl) acetamide 196-1 (20 mg, 0.04 mmol), 4-chloro-6-methylpyrimidine 198-1 (8 mg, 0.06 mmol) Pd (PPh3), i (2 mg, 0.002 mmol ) and K 3 PO 4 (25 mg, 0.12 mmol) in dioxane (0.6 ml) was sparged with nitrogen and heated to 110øC for 2 hours. The salt was removed by filtration and the filtrate was brought to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (6-methylpyrimidin-4- yl) phenyl) acetamide 198. MS m / z 431.20 (M + 1). 1 H NMR 400 MHz (DMSO-d 6) δ 0.59 (s, 1H), 8.16 (d, 2H), 8.04 (d, 1H), 7.98 (s, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 3.45 (m, 1H), 3.11 (s, 2H), 3.58 (b (S, 3H), 2.53 (s, 2H), 2.04 (s, 3H), 2.55 (s, 2H).

Example 46 2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (199)

The mixture of 2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl) acetic acid 193-2 (50 mg, 0.2 mm or 1) and 5- (pyrazin- 2-yl) pyridin-2-amine 86-3 (36 mg, 0.2 mmol) in DCM (1 mL) was added N, N'-diisopropylcarbodiimide (46 mL, 0.3 mmol) the environment. The mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO and then purified by reverse phase HPLC to give 2- (2'-fluoro-3-methyl-2,4'-bipyridin-5-yl ) -N- (5- (p-yrazin-2-yl) pyridin-2-yl) acetamide as white foam. MS m / z 401.2 (M + 1) .1 H NMR 400 MHz (DMSO-d6) δ 11.07 (Q 1 H), 9.25 (d, 1H, J = 1.6 1 Iz), 9.15 (m, 1H), 8.66 (m, 1H), -8.57 (d, 1H, J = 2.4 Hz), 1.47 m, Î ±, H), 8.28 (d, 1H, J = 5.2 MZ), 8.4. (D, 1H, J = 1, 6 Hz), 7.51-7.49 (m, 1H), 7.31 (s, , 1H), 3.82 (s, 2H), 2.3] - (s, 3H).

Example 47 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2- (difluoromethyl) pyridin-4-yl) phenyl) acetamide (201) ΕΡ2403832Β1

Step 1: A mixture of 2- (4- (2- (difluoromethyl) pyridin-4-yl) phenyl) acetic acid 203-5 (30 mg, 0.11 mmol), 1- (4- (6-aminopyridin- 3-yl) piperazin-1-yl) ethanone 111-4 (28 mg, 0.13 mmol), N, N-diisopropylethylamine (99 mL, 0.57 mmol) and O- (7-azabenzotriazol- yl) -N, N, Î'', Î'-tetramethyluronium hexafluorophosphate (65 mg, 0.17 mmol) in DMF (2 ml) was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4- (2- (difluoromethyl) pyridine -4-yl) phenyl) acetamide 201. MS m / z 418.2 (M + 1); ] Δ NMR 400MHz (MeOD) δ 8.61 (d, 1H), 8.25 (d, 1H), 7.91 (d, 1H), 7.80-7.72 (m, 4H), 7.49 (d, 2H), 6.79 (d, 1H), 6.73 (t, 1H), 3.70 (s, 2H), 3.66-3.58 (m, , 52-3.47 (m, 2H), 3.45-3.40 (m, 2H), 2.09 (s, 3H).

Example 48 2- (4- (2- (Difluoromethyl) pyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (203) 138 ΕΡ2403832Β1 fc '. M p-i * g> '0 · *; ¥ ·

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, . .

«SSNS

Step 1; 2-bromo-4-1 (568 mg, 2.0 mmol), 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) -phenyl) acetate 203-2 (580 mg, 2.0 mmol), Pd (PPh 3) 4 (116 mg, 0.1 mmol), N a 2 b- (4 ml), H 2 O (4 ml) and ethanol (1 m d). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 80 ° C for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (5 ml x 3). The combined organic phases were dried over Na 2 SO 4, and concentrated. The residue was purified by flash chromatography on silica gel and eluted with 15% ethyl acetate in hexane to give ethyl 2- (4- (2-bromopyridin-4-yl) phenyl) acetate 203. MS m / z 320.1 (M + 1). Step 2: To a sealed tube Ethyl 2-3- (4- (2- (4-nitrophenyl) phenyl) acetate 203-3 (440 mg, 1.37 mmol) , Ethyl 2-bromo-2,2-difluoroacetate (1.7 mL, 13.7 mmol), Cu (1.3 g, 20.6 mmol) and DMF (5 mL). The reaction mixture was bubbled with nitrogen for 1 minute and

.

5 &gt; Was stirred at 80 ° C for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of Celite and concentrated. The residue was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to give 2- (4- (4- (2-ethoxy-2-oxoethyl) phenyl) pyridin-2-yl ) -Ethyl 2,2-difluoroacetate 203-4. MS m / z 364.2 (M + 1).

Step 3: Ethyl 2- (4- (4- (2-ethoxy-2-oxoethyl) phenyl) pyridin-2-yl) -2,2-difluoroacetate 203-4 (476 mg, 1.3 mmol) was dissolved in 5 mL MeOH and 2 mL 2 N LiOH. The mixture of νmax 3.0 was stirred at 55 ° C for 12 h. After cooling to room temperature, the reaction mixture was dissolved in 5 ml DMF and concentrated 1.5 ml HCl. The solution was stirred at 130 ° C for 3 h. After cooling to room temperature, the solution is dissolved in 5 ml of water and extracted with ethyl acetate (1 x 3). The combined organic phases were dried over Na 2 SO 4, and concentrated. The residue was purified by flash chromatography on silica gel and eluted with 5% MeOH in CH 2 Cl 2 to give 2- (4- (2- (difluoromethyl) pyridin-4-yl) phenyl) acetic acid 203-5. MS m / z 264.1 (M + 1).

Step 4: A mixture of 2- (4- (2- (difluoromethyl) pyridin-4-yl) phenyl) acetic acid 203-5 (70 mg, 0.27 mmol), 5- (pyrazin-2-yl) pyridine -2-amine (55 mg, 0.32 mmol), N, N-diisopropylethylamine (139 ml, 0.80 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' tetramethyluronium hexafluorophosphate (152 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2- (4- (2- (difluoromethyl) pyridin-4-

yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide 203. MS 140 ΕΡ2403832Β1 ΕΡ2403832Β1 m / z 418.2 (M + 1); 1 H NMR (CDCl 3) δ 8.99 (d, 1H), 8.90 (dd, 1H), 8.70 (d, 1H), 8.63 (dd, 1H), 8.53 (S, 1H), 7.84 (s, 1H), 7.70-7.68 (m, 2H), 7.62 (s, 7.60-7.49 (m, 2H), 6.70 (t, 1H), 3.87 (s, 2H).

Example 49 2- (2 ', 3-Difluoro-2,4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (205) The invention relates to a process for the preparation of a compound of the formula (II): ## STR1 ## in which R 1 is as defined in formula (I). S-3 S-2 S-2 S-2

. &lt; / RTI &gt; Νή.1- ____ · Λ Λ Λ ϊϊ - Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ

Compound 205

Step 1: In a sealed tube, a mixture of 5-bromo-2-chloro-3-fluoropyridine 205-1 (631 mg, 3 mmol), zinc (II) chloride (2-tert-butoxy-2-oxoethyl) at 0.5 M 205-2 in ether (6.6 mL, 3.3 mmol), Pd (dba) 2 (87 mg, 0.15 mmol), 1,2,3,4,5-penta-phenyl (12 ml) under argon was stirred at 70 ° C for 18 hours. After being cooled to the temperature The solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluted with 30% ethyl acetate in hexane to give tert -butyl 2- (6-chloro-b-fluoropyridin-3-yl) acetate butyl ester as a brown oil. MS m / z 246.1 (M + 1).

Step 2: To a flask containing tert-butyl 2- (6-chloro-5-fluoropyridin-3-yl) acetate 205-3 (370 mg, 1.5 mmol), 2-fluoropyridin-4-ylboronic acid 205- 4 (318 mg, 2.25 mmol), Pd (OAc) 2 (17 mg, 0.075 mmol), 1-hex-1-phosphono-2 ', 6'-dikethyl. (62 mg, 0.15 mmol), K 3 PO 4 (800 mg, 9 mmol) under argon was added 2-butanol (1.5 mL). The reaction mixture was stirred at 100 ° C for 10 hours. After being cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na 2 SO 4, and concentrated to dryness by rotary evaporation. The crude material was purified by flash chromatography on silica gel, eluted with 20% ethyl acetate in dichloromethane to give 2- (2 ', 3-difluoro-2,4'-bipyridin-5-yl) acetate tert-butyl ester as a yellow oil. MS m / z 307.1 (M + 1).

Step 3: A mixture of tert-butyl 2- (2 ', 3'-difluoro-2,4'-bipyridin-5-yl) acetate 205-5 (248 mg, 0.8.1 mmol) and TFA (0.8 ml) in DCM (0.8 ml) was stirred at room temperature for 3 hours. The solution had the pH adjusted to around 12 by Na 2 CO 3 and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by 1 N aqueous HCl solution and stirred for 15 minutes. The solvents were evaporated and the remaining solid was extracted with 20% methanol in ethyl acetate and filtered to remove the insoluble. The filtrate was concentrated to dryness by rotary evaporation to give 2- (2 ', 3-difluoro-2,4-bpyridin-5-yl) -carbamic acid 205-6, which was used directly for the following stage. MS m / z 211.1 (M + 1).

Step 4: A mixture of 2- (2 ', 3-difluoro-2,4'-bipyridin-5-yl) acetic acid 205-6 (50 mg, 0.2 mmol), 5- (pyrazin-2-yl ) pyridine-2-amine 86-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4- (dimethylamino) pyridine (4 mg, 0.04 mmol) in DMF (0.9 ml) was stirred at room temperature for 10 hours. The crude product was filtered and the filtrate was subjected directly to reverse phase HPLC to give 2- (2 ', 3-difluoro-2,4-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridine-2-yl) acetic acid as white solid. MS m / z 405.2 (M + 1) r] H NMR = 400 MHz (DMSO-d6) δ 11.16 (s, 1H), -1.1 (d, 1H), 9.12 ( d, 1H), 7.74 (dd, 1H), 8.63 (d, 1H), 8.61-8.60 (m, 1H), 8.52 (dd, 1H), 8.41 (d, 1H), 8.21 (1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.64 / 21 D.

Example 50 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetamide (206) 143 ΕΡ2403832Β1

36-5 28g-5

Step 1: To a sealed tube was added 5-bromo-2-iodobenzonitrile 206-1 (500 mg, 1.6 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (229 mg, 1.6 mmol),

Pd (PPh 3) 4 (94 mg, 0.08 mmol), Na 2 CO 3 (516 mg, 4.9 mmol), toluene (2 mL), H 2 O (2 mL) and ethanol (0.5 mL) was stirred at 120 ° C overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 ml x 3). The combined organic phases were dried over Na2 SO4 &gt; 4, and concentrated. The residue was purified by flash chromatography on silica gel and eluted with 15% ethyl acetate in hexane to give 5-bromo-2- (2-fluoropyridin-4-yl) benzonitrile 206-3. MS m / z 277.1 (M + 1).

To a sealed tube was added 5-bromo-2- (2-fluoropyridin-4-yl) benzonitrile 206-3 (42 mg, 0.16 mmol), (2-tert-butoxy-2-oxoethyl chloride ) Zinc (II) at 0.5 M 86-5 in ether (0.46 ml, 0.23 mmol), Pd (dba) 2 (4.4 mg, 0.008 mmol), Q- phos (10, 8 mg, 0.015 mmol) and THF (1 mL). The reaction mixture was bubbled with nitrogen for 1 minute Ρ2403832Β1 and stirred at r.t. 100 ° C for 1 week. After cooling to room temperature, all solvent was evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2 SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to give 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetate of tert-butyl 206-5. MS m / z 313.2 (M + 1).

Step 3: A mixture of tert-butyl 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetate 206-5 (35 mg, 0.11 mmol) and TF A (0.5 ml) in DMF (3 ml) was stirred at room temperature for 5 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) cyclohexane 206-6, was dissolved in DMF (2 mL). (23mg, 0.13mmol) and DIEA (98æl, 0.56mmol) were added to the solution prior to O - (7-azabenzotriazol-1-yl) -phenylacetic acid hexafluorophosphate yl) -α, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (64 mg, 0.17 mmol). The mixture was stirred at room temperature overnight. The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4- (2-fluoropyridin-4 -yl) -phenyl) -acetamide 206. MS m / z 4: 11.2 (M + 1); 1 H NMR (m, 1H), 8.66 (dd, 1H), 8.52 (d, 1H), 8.42 (dd, 1H), 8.32 (d, 1H), 8.25 (d, 1H), Î'92 (d, 1H), 7.81 (dd, 1H), 7.64 (d, 1H), 7 , 1.58 (dt, 1H), 7.28 (s, 1 H), 3.93 (s, 2H) Example 51 N- (5- (4-Acetylphiperazin-1-yl) 2-yl) -2- (3-fluoro-4- (2-fluoropyrimidin-4-yl) phenyl) acetamide (207) 145 ΕΡ2403832Β1 Bf-

2D7-1

Pd (PPt) 4

Na 2 CO 3 ToWOH 20 / EtOH 205-4

αζη '- ^ γ0 ^ o'

Ptf (d ba yCT -Q -Phos

TNF 86-5 207-5

To a sealed tube was added 4-bromo-2-fluoro-1-iodobenzene 207-1 (600 mg, 2.0 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (282 mg, 0 mmol),

Pd (PPh 3) 4 (116 mg, 0.1 mmol), Na 2 CO 3 (636 mg, 6.0 mmol), toluene (2 mL), H 2 O (2 mL) and ethanol (0.5 mL) was stirred at 120 ° C overnight. After cooling to room temperature, the solvents were evaporated and the combined organic extracts were dried (Na2 SO4) and evaporated. The residue was purified by silica gel eluting to give 4- (4-bromo) ml x 3) The phases were dried over Na 2 SO 4 and concentrated by flash chromatography with 15% ethyl acetate in hexane 2-fluorophenyl) -2-fluoropyridine 207-3, MS m / z 270 , 1 (M + 1).

To a sealed tube was added 4- (4-bromo-2-fluorophenyl) -2-fluoropyridine 207-3 (210 mg, 0.76 mmol), (2-tert-butoxy-2-oxoethyl) (22 mg, 0.04 mmol), Q-phos (54 mg, 0.6 mmol), potassium carbonate 07 mmol) and THF (5 mL). The reaction mixture was bubbled with SLZoto for 1 minute and stirred at 100 ° C for 1 hour. After cooling to room temperature, all solvent was evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel and eluted with 20% ethyl acetate in hexane to give tert -butyl 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) acetate butyl ester 207-5. MS m / z 306.2 (M + 1).

Step 3: A mixture of tert-butyl 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) acetate 207-5 (100 mg, 0.33 mmol) and TFA (0.5 mL ) in DCM (3 ml) was stirred at room temperature for 5 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) acetic acid 207-6 (50 mg, 0.20 mmol) was dissolved in DMF (2 mL), - (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone (53 mg, 0.24 mmol) and DIEA (174 uL, 1.0 mmol) were added to the solution before O- ( 7-azabenzotriazol-1-yl) -N, N, N, N '-tetramethyluronium hexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N- (5- (4-aethoxypyridin-1-yl) pyridin-2-yl) -2 '- (3- 4-yl) -phenyl] acetamide 207. MS m / z 45 2.2 (M: + 1) / n NMR 400 MHz (MeOD) δ 8.21 (d, 1H), δ (t, 1H), 7.88 (d, 1H), d 5.7-7.51 (m, 1H), 7.48- 7.45 (m, 1H), 7.31 (dd, 1H), 7.3 - N, 21 (m, 3H),, 3.75 (s, 2 H), 3.68 L-Zn), 3.63 (t, 2H), 3.14 (t, 2H), 3.09 (t, 2H); 2H, J = 5; 2 Hz), 3.09 (s, 3H), 147 ΕΡ240383261

Example 52 2- (2'-fluoro-2,4 '-bipyridin-5-yl) - (- ((o- (pyrazin-

208-120-4

DCC, 4-DMAP EMF 208-2

Step 1: To a flask containing ethyl 2- (6-chloropyridin-3-yl) acetate 208-1 (300 mg, 1.5 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (318 mg, 2 , 25 mmol),

Fd (OAi) 2 (1 mg, 0.075 mmol), 2-cyclohexylphosphino-2 ', 6' 'C for 10 hours. , 15 mmol), potassium carbonate (800 mg, 9 mmol) under argon was added 2-butanol (1.5 ml). The reaction mixture was cooled to room temperature, partitioned with ethyl acetate, washed with water and brine The crude material was purified by flash chromatography on silica gel, eluted with 40% ethyl acetate in dichloromethane to give 2- (2'-fluoro-2 , 4'-bipyridin-5-yl) acetate 208-2 as a yellow MS m / z 261.1 (M + 1).

Step 2: A mixture of ethyl 2- (2'-fluoro-2,4'-bipyridin-5-yl) acetate 208-2 (93 mg, 0.36 mmol) and NaOH (.57 mol. mmol) in THF (0.5 mL) and water (0.5 mL) was stirred at 65 ° C for 3 hours. After being cooled to ambient temperature, the mixture was treated with 3N aqueous HCl solution to adjust the pH to about 3, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted with 20% methanol in ethyl acetate. The organic portion was concentrated to give 2- (2'-fluoro-2,4'-bipyridin-5-yl) acetic acid as a pale white solid. MS m / z 233.1 (M + 1).

Step 3: A mixture of 2- (2'-fluoro-2,4-bipyridin-5-yl) acetic acid, 208-3 (42 mg, 0.18 mmol), 31 mg, 0.18 mmol), 1 C -! - &gt; 0.22 mmol) and 4 mmol) in. DMF (0.9 ml) for 10 hours. (4 mg, 0.03 g) was stirred at ambient temperature and the crude product was filtered and the filtrate was purified by flash chromatography (silica gel). of reverse phase HPLC to give 2- (2-fluoro-2,4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide as white solid M / z 387.1 (M + D) + H NMR 400 MHz (DMSO-d6) δ: 11.14 (S / 1H), 9.31 (d, 1H) 9.11 (d, 1H), 8, 73-8, 71 (m, 2H), 8.62 (d, 1H), 8.52 (dd 1H), 8.36 (d, 1H), 8.28-8.17 , 2H), 8.06-8.02 (m, 1H), 7.95 (dd, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 3.94 (s, 2H).

Example 53 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-2,4'-bipyridin-5-yl) acetamide (209)

HATU / DIEA DMF

compound 209 step

The mixture of 2- (2'-fluoro-14β) -pyrrolidin-5-yl) acetic acid, 208-3 (42 mg, 0.18 mmol), 1- (4- (6β, 20β) -1-Piperazin-1-yl) ethanone 111-4 (4H, m, 18 mmol), o- (7-azabenzotriazol-1-yl) -N, N, N ' , N'-tet. (HATU, 68 mg, 0.18 mmol) were added mFU (1 ml) and diisopropylethyl amine (DISA, 0.15 ml, 0.9 mmol) and the mixture was stirred at room temperature overnight. The crude product, a clear solution of DMF, was subjected directly to reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-2- , 4'-bipyridin-5-yl) acetamide as white solid. MS m / z 435.2 (M + 1); NMR 400MHz (DMSO-d6) δ 10.65 (s, 1H), 8.69 (d, 1H), 8.36 (d, 1H), 8.15 (d, 1H), 8.05- 8.02 (m, 2H), 7.94-7.90 (m, 2H), 7.81 (s, 1H), 7.42 (dd, 1H), 3.83 (s, , 57-3.54 (m, 4H), 3.15-3.13 (m, 2H), 3.0-3.06 (m, 2H), 2.03 (s, 3H).

Example 54 2- (2 ', 3-Difluoro-2,4'-bipyridin-5-yl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide (210)

Step 1: To a mixture of 4- -R.-; (pyridazin-3-yl) -pyridin-2-yl) -acetic acid methyl ester, (17 mg, 0.1 mmol), α- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU, 38 mg , 0.1 mmol) were added DMF (0.5 mL) and diisopropylethyl amine (DIEA, 0.05 mL, 0.3 mmol) and the solution was stirred at -20 DEG C. The solution of crude DMF was directly purified by means of of reverse phase HPLC to give 2- (2 ', 3-difluoro-2,4' -bipyridin-5-yl) -N- (5- (pyridazin-3-yl) pyridyne -2-i-1-yl) acetamide as a white solid MS m / z 401 (M + 1); 1 H NMR (d, (D, 1H), 8.61 (m, 1-H), 8.56 (dd, 1H), 8.41 (d, 1H), 8 (Dd, 1H), 9.86 (m, 1H), 7.81 (dd, 1H) , 7.65 (s, 1H), 4.02 (s,

Example 50 N- (5- (4-Acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetamide (211)

Step 1: 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetic acid 206-6 (50 mg, 0.20 mmol) was dissolved in DMF (2 mL). 1- (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone (52 mg, 0.23 mmol) and DIEA (170 æl, 0.98 mmol) were added to the solution prior to hexafluorophosphate - (7-azabenzotriazol-1-yl) -α, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (111 mg, 0.29 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by HPLC method to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-cyanophenyl) -4- - (2-fluorophenyl) -4-phenyl-1-acetamide 211. MS m / z 459.2 (M + D); NMR (400MHz, CDCl 3): δ (CDCl 3): δ 7.8 (d, 1H) , 7.71 (d, 1H), 7.62 (dt, 1H), 7.49 (s, 1H), 7.42 (dd, 1H), 7.81 (S, 2H), 3.59-3.54 (m, 4H), 3.15 (t, 2H), 3.3 (t, 2H), 2.04 (s, 3H) ).

Example 56 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyrimidin-2-yl) acetamide (212)

HATU / DÍ EA / DMF

Step 1: 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) acetic acid 207-6 (50 mg, 0.20 mmol) was dissolved in DMF (2 mL), 5- pyrazin-2-yl) pyridin-2-amine (41 mg, 0.24 mmol) and DIEA (174 μL, 1.0 mmol) were added to the solution prior to O- (7-azabenzotriazol-1-yl) hexafluorophosphate -N, N, N ', N'-tetramethyluronium hexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyrazin-2-yl) pyridin-2 -yl) acetamide 212. MS m / z 404.1 (M + 1); 1 H NMR 400.00 (DMSO-d 6) δ 11.10 (s, 1H) 9.31 (d, 1H), 9.11 (dd, 1H), 8.63 (d 1H), 8.52 (dd, 1H), 8.34 (1H, 1H), 8.21 (d, 1H) (m, 2H), 7.33-7.34 (m, 3H), 3.89 (s, 2H).

Example 57 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) -N- (5- (pyridazin-3-yl) pyridin-2-yl) acetamide (213) 152 ΕΡ2403832Β1

Step 1: 2- (3-fluoro-4- (2-fluoropyridin-4-yl) phenyl) acetic acid 207-6 (37 mg, 0.15 mmol) was dissolved in DMF (2 mL), 5- pyridazin-3-yl) pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to

solution before O - (7-azabenzotriazol-1-yl) -N, N, N ', Ν' -tetramethyluronium hexafluorophosphate (86 mg, 0.23 mmol). A mixture of temperature and humidity; it ite iqi t

The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC meOH to give 2- (3-fluoro-4- (2-fluoropyrimidin-4-yl) phenyl) -N- (5- (pyr idazin-3-yl) pyridaz η-2-yl) to ketamide 213. MS m / z 402 (M + 1)); 1 H NMR (400 MHz, CD 3 OD): δ 11.11 (s, 1 m, 9H), 9.13 (dd, 1H), 8.55 (dd, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.83-7.78 (m, , 71-7.65 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.35 (m, 3H), 3.90 (s, 2H).

Example 58 2- (3-cyano-4- (2-fluoropyidin-4-yl) phenyl) -N- (5-pyridazin-3-yl) pyrimidin-2-yl) 214)

Step 1: 2- (3-cyano-4- (2-fluoropyridin-4-yl) phenyl) acetic acid 206-6 (38 mg, 0.15 mmol) was dissolved in DMF (2 mL), - (pyridazin-3-yl) pyridin-2-amine (31 mg, 0.18 mmol) and tetrahydrofuran (131 uL, 0.75 mmol) were added to the solution of O- (7-aza-benzotriazole-1-carboxylic acid hexafluorophosphate -α, Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC. p. 1- (3-cyano-4-N- (5- (pyr-d &lt; 3.2 X p-3-yl) pyridin-411.2 (M + D; 1 H NMR: 9.23 (dd, 1H), 9.13 (d, 1H), 8.30 (dd, 1H), 8.23 (d, 1H), 7.74 (1H, , 2 H). (2-Fluoropyrimidin-4-yl) phenyl) -yl) acetamide 214. MS m / zz (DMSO-d 6) δ 11.14 (s, 1H), 8.56 (dd, 1H), 8.42 (d, 1H), 1.00 (t, 1H), 7.50 (s, 1H), 3,97 ,

Example 59 N- (6- (3-fluorophenyl) pyridin-3-yl) -2- (S, S-dioxo-6-thiomorpholinopyridin-3-yl) acetamide (219)

ΐ: Sy Sy Sy A A A ...... ...... ...... ...... ...... ...... ...... Sy Sy Sy Sy Sy Sy Sy Sy Sy Sy Sy Sy Sy d d d

Step 1. To a round bottom flask were added 2-chloro-5-nitropyridine (3.2 g, 20 mmol), (3-j uoroanyl) boronic acid (2.8 g, 20 mmol), Pd (20 ml) and Na 2 CO 3 (2 M, 2 ml). The reaction mixture was bubbled with nitrogen for 2 minutes and subjected to reflux at 110 ° C for 2 hours. After cooling to room temperature, the reaction residue was diluted with ethyl acetate (500 mL) and washed with saturated aqueous NaHCO 3 solution and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by flash chromatography on silica gel, eluting with 50% to 100% ethyl acetate in hexane 2- (3-fluorophenyl) -5-nitropyridine as yellow solid. MS m / z 219.1 (M + 1).

Step 2. To a round bottom flask was added 2- (3-fluorophenyl) -5-nitropyridine (3.8 g, 17 mmol), Pd / C (0.5 g) and methanol (100 ml). The reaction was stirred for 4 hours under hydrogen atmosphere by the union of one. hydrogen balloon. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give 6- (3-fluorophenyl) pyridin-3-amine 219-1 as brown solid. MS m / z 18 9.1 (M + D.

Step 3. A mixture of thiomorpholine (1.03 g, 10.0 mmol), 5-bromo-2-iodopyrimidine. (200 mg, 0.2 mmol), xanthones (510 mg, 0.6 mmol) and t-BuONa (1.44 g, 15 mmol) in toluene (3.69 g, 13 mmol), Pd2 (dba) 50 ml) was stirred under argon at 98 ° C for 3 hours. After being cooled to room temperature, m. The residue was purified by chromatography on silica gel eluting with ethyl acetate. The material filtered the residue was subjected to column chromatography with 0-5% ethyl acetate in the eluent to give 4- (5-bromopropyl) -2-hydroxybenzylidene-2-yl) thiomorpholine as a solid. - (5-bromopyrimidin-2-yl) sulfonamide (102 mg, 0.46 mmol, 0.9 mmol) and 4-L .. (45 mL) was stirred cooled until finalized through

Step 4. A mixture of 1-yl) thiomorpholine 219-2 (2.37 g, 9.1 mmol), Pd (OAc). (0.6 g, 18.3 mmol) in toluene-sulfuric acid at 9 DEG C. for 1 hour at room temperature, the mixture was recrystallized from ethyl acetate and washed with ethyl acetate. The filtrate was evaporated and the residue was subjected to flash column chromatography to give diethyl 2- (6-thiomorpholinopyridin-3-yl) malonate 219-3.

Step 5. 2- (6-Morpholino-pyridin-3-yl) malonate 219-3 (564 mg, 1.67 mmol) was stirred with NaOH (334 mg, 8.35 mmol) in dioxane (5 mL) and water (5 mL) ml) for 4 hours. The HCr solution was added to adjust the pH to about 1 and the reaction mixture heated at 88 ° C for 1 hour. Then Na 2 CO 3 was used to adjust the pH to around 4 before the solvents were evaporated. The residue was extracted with ethyl acetate and the organic extract dried over Na 2 SO 4 and concentrated by rotary evaporation. Purification with reversed-phase HPLC afforded 2- (6-thiomorpholinopyridin-3-yl) acetic acid 219-4.

Step 6. A mixture of 2- (6-thiomorpholinopyridin-3-yl) acetic acid 219-4 (92 mg, 0.39 mmol), 6- (3-fluorophenyl) pyridin-3-amine 219-1 (73 mg, , HATU (162 mg, 0.43 mmol) and DIEA (104 mL, 0.6 mmol) in DMF (1.0 mL) was stirred at room temperature overnight and was not redistributed between water (30 ml) or ethyl acetate (4 ml). The organic phase was dried over Na2SO4 and concentrated by means of spinning evaporation. Chromatography on silica gel in acetonitrile (EtOAc / hexanes of 156 ÅΡ2403832Β1 1:10 to 2: 1 as eluent) gave N- (6- (3-fluorophenyl) pyridin-3-yl) -2 --- (6-thiomorpholinopyridin-3-yl) acetamide 219-5 as a solid. 3-yl) -2- (6- (11M) (mg, QN) COOH. The mixture was stirred at room temperature for 30 minutes, washed 4 times and then cooled to room temperature. of N 1- (6- (3- (3- (S, S-dioxo-6-SODI) and 1: 1: 1 (s, 1H); J (d, 1) (m, 1H), 7.22 (d, 1H), 3.61 (s,

Step 7. N- (6- (3-fluorophenyl) pthiomorpholinopyridin-3-yl) acetamide 219-5 (114 mmol) was treated with mCPBA in DCM (2 mL) stirred at room temperature and the mixture was diluted with acetate of ethylene with 5% Na 2 CO 3 solution, dried over Na 2 SO 4 &lt; by means of rotary evaporation. The residue was purified by reverse phase HPLC (fluorophenyl) pyridin-3-yl) -thiomorpholinopyridin-3-yl) acetamide 219 as 396.3 (M + 1); (DMSO-d 6) δ 8.82 (d, 1 H), 8.16 (dd, 1 H), 8.11 (d, 1 H), 7.92-7.80 (m, 2 H), 7.60 (dd, 1 H), 7.5 ((m, 1 H), 7.02 (d, 1 H), 4.06-4.01 (m, 4 H), 3 , 61 (s, 3, 10-3.05 (m, 4 H).

EXAMPLE 60 2- (2'-Fluoro-3-methyl-2,4'-bipyridin-5-yl) -N- (5- (pyridazin-1-yl) (2'-fluoro-3-methyl-1H-indol-3-yl) -1,2,3,4- (25 mg, 0.1 mmol) and 5- (pyridazin-3-yl) pyridin-2-amine 145-3 (17 mg, 0.1 mmol) in DCM (1 ml) was added N, N'-Diisopropylcarbodiimide (22 157 ΕΡ2403832Β1

ml, 0.15 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO and then purified by HPLC from step (a) to 2- (2'-fluoro-3-methyl-4'- biphenyl-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide as white solid. MS m / z 40 + nZ-t 1-1: 1); Δ NMR 400MHz (DMSOd 6) δ 11.09 (s, 1H), 9.17 (dd, 1H), 9.07 (d, 1H), 8.51 (dd, 1H), 8 (D, 1H), 8.25 (dd, 1H), 8.18 (d, 1H), 7.76 (m, 1H), 7.71 (d, 1H) , 1H), 7.51 (m, 1H), 7.31 (s, 1H), 3.83 (s, 2H), 2.31 (s, 3H).

Example 61 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-methyl-2 '- (trifluoromethyl) -2,4' bipyridin-5-yl) acetamide (222) ci

148-1

Acetylpiperazin-1-yl) pyridin-2-yl) -2- (6-chloro-5-methylpyridin-3-yl) acetamide 148-1 0-23 mg, 0.6 mmol), Pd (OAc) 2 (61 mg, 0.26-Dimethoxy-1.1 mg, 0.032 mmole) 2- (trifluoromethyl) pyridine- (3.6 mg, 0.016 mmol), biphenyl-2-yl) dicyclohexylphosphine (13.0 g), and the contents thereof were dried over sodium sulfate (1.0 g) and stirred at 0 ° C The residue was dried (Na2 SO4), dried (Na2 SO4), dried (Na2 SO4) and evaporated to dryness was added overnight. After ambient, the mixture was ethyl acetate (8 ml x was dried over Na 2 SO 4, purified by reverse phase HPLC to give N- (4-acetylpiperazin-1-yl) pyridin-2-yl ) -2- (3-methyl-2 '- (trifluoromethyl) -2,4-ij) pyridin-5-yl) acetamide MS m / z 498.8 (M + 1); NMR (400 MHz, CDCl3) δ 8.81 (d, 1H), 8.51 (d, 1H), 8.35 (s, 1H), Î'11.11 (d, 1H), 7.91 1H), 7.89 (d, 1H), 7.68-7.64 (m, 2H), 7.30 (dd, 1H), 3.80-3.75 , 63 (t, 2H), 3.14 (t, 2H), 3.11 (t, 2H), 2.39 (s, 3H), 2.14 (s, 3H). Example 62 2- (3-methyl-2 '- (trifluoromethyl) -2,4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide (223 )

To a sealed tube were added 2- (6-chloro-5-methylpyridin-3-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) acetamide 86-8 (85 mg, 2- (trifluoromethyl) pyridin-4-ylboronic acid (48 mg, 0.25 mmol), Pd (OAc) 2 (2.8 mg, 0.013 mmol), 2,6-Dimethoxy -1'-biphenyl-2-yl) dicyclohexylphosphino (10.2 mg, 0.025 mmol) and K 3 PO 4 (159 mg, 0.75 mmol). The tube and its contents were then purged with. nitrogen. After degassed toluene (1.0 ml) was added, the mixture was stirred at 10 ° C for 2 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate (8 ml x 3). The combined organic phases were dried over Na2 SO4 &lt; j. and concentrated. The residue was purified by reverse phase HPLC to give 2- (3-methyl-2 '- (trifluoromethyl) -2,4'-bipyridin-5-yl) (5- (pyrazin-2-yl) pyridin- 2-yl) acetyl] -2,3-

MS m / z 460, 8 (M + 1); 1 H NMR (CDCl 3) δ 9.01 (d, 1H) P fwr 95 (s, 1H), 8.81 (d, 8.76 (s, 1H), 8.63 (dd, 1H) (M, 2H), 8.39 (s, 2H), 7.89 (s, 1H), 7.69-7.65 (m, 2H), 3.84 (s, 2H), , 3 H). Example 63 N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (4-cyano-3- (2-methylpyridin-4-yl) phenyl) acetamide (237)

• (CF3SO2) 2o- ΌΗ

NEt3 DCM

237-1

(Ppm)). The title compound was prepared from the title compound as colorless oil. N + Zn (CN [2] -, DMI;

SnBu, 237-3

HATU / DIEA, DMF

237-2

Compound 237

Step 1. To a mixture of 2- (3-chloro-4-hydroxyphenyl) acetic acid (560 mg, 3.00 mmol), trifluoromethanesulfonic anhydride (888 mg, 3.15 mmol) in DMF (30 ml) was added triethylamine (1.1 mil, 8.06 mmol) and the mixture was stirred at room temperature. Washed with 1N HCl (30 mL x 2), dried over Na 2 SO 4 and concentrated by rotary evaporation to give 2- (3-chloro-4- (trifluoromethylsulfonyloxy) phenyl) acetic acid 237-1 (749 mg, , crude) which was used directly for the reaction without further purification.

Step 2. A solution of 2- (3-chloro-4- (trifluoromethylsulfonyloxy) phenyl) acetic acid 237-1, 1- (4- (6- (1H-2β, 40β) piperazine-1-yl] geanone (0.51 mmol), HATU (232 mg, 0.61 mmol) and DIEA (0.26 mL, 1.49 mmol) in DMF (2.0 mL) was stirred at The solution was subjected directly to reverse phase HPLC for 4 - (5 - (4-azetidazol-1-yl) pyrrole-2-carboxylic acid trifluoromethanesulfonate A mixture of 4- (2- (5- (4-acetylpiperazin-1-yl) pyridin-2-ylamino) -2-oxoethyl) -2-oxoethyl] -2-oxoethyl) -2-chlorophenyl tri- (30 mg, 0.255 mmol), Pd (PPh 3) 4 (14 mg, 0.012 mmol) in DMF (0.6 mL) was added at 80 DEG C. argon for 96 hours. And cooled to room temperature, filtered through celite, washed with ethyl acetate, and concentrated by evaporation of solvents. The residue was subjected to purification by reverse phase HPLC to give N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-chloro-4-cyanophenyl) acetamide as a 237- 3.

Etc.

A mixture of N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (3-chloro-4-cyanophenyl) acetamide as the solid 237-3 (17 mg, 0.043 mmol), 2- (24.5 mg, 0.064 mmol), Pd (PPh3), a (5 mg, 0.0043 mmol) in DMF (0.6 ml) was stirred at 118 ° C Under argon overnight. After being cooled to room temperature, it was filtered through celite while washing and diluted with ethyl acetate (3N H). It was then washed with water (40 ml) and extracted with 0.5 N HCl (30 ml) . After the aqueous extraction was treated with Na2 CO3 to have the pH adjusted to ca. aqueous the extract was extracted with ethyl acetate (3q mq combined organic phases were dried to X2 phase). Concentrates are concentrated by means of rotary

Na 2 SO 4, residue chromatographed on silica gel in c:

with MeOH 161 ΕΡ2403832Β1 ΕΡ2403832Β1 L ± ± c cet pi pi pe pe £ 3. (M + 1) [M + 1] [M + 1] + 1% [M + 1]. 53 ___H! (m, 4H), 400 (m, 3H), 8.62 (d, 1 H) ), 8.08 (bs, 1 H), 7.91 (d, 1 H), 7.79 (d, 1 H), H), 7.34 (Ι'- 31- 7.26 (m, 2 H), 3.75 (m, 2 Η), 3.65-3.60 (m, 2 Η),

Example 64 2- (2-methyl-2, 4'-bipyridin-4-yl) -α- (5- (pyrazin-2-yl) pyridin-2-yl)

EtOAc (1: 1) was added to a flask containing 2- (2-chloropropyridin-4-yl) -3-keta-1-one 238-1 (1.00 g, 5.38 mmol). 2-methyl-4- (tr1-but-11-yl) pyridine (Z, Rb), Pd (PI3h3) 4 (494 mg, under argon was added DMF (15 ml). The reaction mixture was stirred at 120Â ° C for 10 hours, after which the reaction mixture was cooled to room temperature, the mixture dilution 3: 1 ethyl acetate, 1.0. , and concentrated to dryness in vacuo. The title compound was obtained as a white solid. The crude material was purified by flash chromatography on silica gel, 1% vol. With 5% methane in dichloromethane to give 2- (2'-tetrazol-2-yl) methyl] -2,4'-bipyridin-4 -yl) acetate 238-2 as dark orange oil. MS m / z 243.1 (M + 1).

Step 2: A mixture of methyl 2- (2'-methyl-2,4-bipyridin-4-yl) acetate 238-2 (621 mg, 2.56 mmol) and NaOH (409 mg, 10.24 mmol ) in 1,4-dioxane (6 ml) and water (6 ml) stirred at 80 ° C for 3 hours. After being cooled to room temperature, the mixture was treated with 3N aqueous HCl solution to adjust the pH to around 4, and then stirred for 15 minutes. The resulting solution was evaporated to dryness; and the remaining solid was extracted with 20 ml of methanol in ethyl acetate. The concentrated organic extract affords 2- (2'-methyl-2,4 '-bipyridin-4-yl) acetic acid 238-3 as pale white solid MS m / z 229.1 (M +

Step 3: A mixture of 2- (2,2-methyl-2,4'-piperidin-4-yl) acetic acid 238-3 (46 mg, 0.2 mmol), 5- (pyrazin-2-yl) pyridin- amine 86-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4- (dimethylamino) pyridine (4 mg, 0.04 mmol) in DMF ml) was stirred at room temperature for 10 hours.The crude product was filtered to remove insoluble matter and the filtrate was subjected directly to reverse phase HPLC purification to give 2- (2'-methyl-2,4'-bipyridine 4-yl) -N- (5- (pyrazin-2-yl) pyridin-2-yl) -acetamide 238 as white MS m / z 383.1 (DMSO-d6) δ 1.1.14 (s, 1H), 9.30 (d, 1H), Î', 11 (dd, 1H), 8.73 8.71 (m, 1H), 7.00 (d, 1H), 8.62 (d, 1H), 8.56 (d, 1H), 8.52 (dd, 1H), 8.21 ( d, 1H), 8.09 (s, 1H), 7.93 (S, IR), 7.84 (dd, 1H), 7.45 (dd, 1H), 3.95 (s, 2H), 2.56 (s, 3H).

The exemplified compounds are summarized in Table 1, with IC50 values measured using reporter assays

Wnt-Luc. 163 ΕΡ2403832Β1

Table 1

Comp. MS structure (m / z) (M + 1) LC retention time (min) IC 50 (nM) 1 χ / IH 485.30 1.465 1 f 5 H 398.2 1.48 3 ZR 376.10 1.445 1.6 4 r? H &gt; 1 Γ * Ν sAn ^ o H 385.2 1,342 774 5 v Ti u ^ Vh / 0 N 42 426,12 1,730 481,3 164 ΕΡ2403832Β1 6 ΛΟΟ- * Ο7 \ = 5V / \ V -. 390.12 1.581 0.57. H &lt; ν. N C T YH / 0 N'O "° 427.12 1.573 405.98% q / Ύ" νη O çy N 424.07 1.195 13.89% / V-NH Υ-λ '/)) 36 36 36 36 364,08 1,526 18,6 10 / = N M vP &quot; fPY Y-NH 346.09 1, 487 5 81.4 165 ΕΡ2403832Β1 11 ° Q_ N 377.10 1.361 20.0 12 0 y y - - - 40 40 40 40 40 40 40 404,14 1,562 2,4 ** s UL / "Nj> LQK \ = N 391.12 1,372 15.1 14 0 Q Vn (/ ^ IS3 391.12 2.098 54.9 15 0 S &quot; 3 \ N = \ ΙμλΗ} H 373.10 0 , 92 4 669 16 fl ^ 'Λ / ^ ν Η 373.10 1,203 110.6 166 ΕΡ2403832Β1 17 404.14 1.552 CO 18 N / H 387.12 1.590 22.2 19 fj 3-NH 3 CO 4 1.45 211.1 20 / = N and / or N / O 0 FV + NH 4 379.10 1,528 114, 9 21 H 340.14 1.258 834.8 22 - (-) - N '- (+) - N' - (N ' f - - 1,515 1243 167 ΕΡ2403832Β1 23> v = 391,12 1,454 34.6 2 4 XXanaVQ H 400.14 1.777 5.0 9.46 - H H 386.12, 1.686 19, 5 26 '' '' '' '' '' '' '' '' '' '' '' '' '' '' 380.17 2.518 8 0 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, , 4 29 H 386.12, 1 641 Ί QC, .1.0,. 168 ΕΡ2403832Β1 30 rw = 406.11 2.051 19.0 31 / = Ν / S ^ 1 | -NH N 404.14 1.57 6 28.0 32 Ν Ν S / / / 400.14 1.776 16.0 33 H Δ. · · 1 1 1 Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ 3 β N J0) H 380.17 1.916 <0, 11 169 ΕΡ2403832Β1 ο η • j / η, η Η 36 /, 15 1, 934 28 38 Η 394.18 1.441 0 r 85 39 Αλνα / Η 41 0 1 p 1,591 1.4 40 Ν Α Λ Α Α Α Α Α Α Α Α Α Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η 410,18 1,508 92,9 41 Ν Ι Ι ° ° ° Η λνλΑ Η 381.16 1.747 4.0 43 Ν ^, Ν &lt; ίΓ '^ || ΑΑγ ^ 0 N ^ yAA H 381.16 1.016 4.7 44 F! H Γ 454.11 2.086 2.5 170 ΕΡ2403832Β1 45 Η 394.18 1.635 Γ Γ Γ J J J J J J Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν 47 Ν ^ | Ιΐ Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η 381,16 0,892 0,07 48 14 50 Ν Μ Μ Μ Μ Μ Μ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ ΑΧ Α κ,, Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 398.16 1.594 0.89 5 6 o H H 398.16 1, 651 <0.0 9 57 < H 416.24 0.764 40.38 fA), χχΑχχ, NAff's's's's k k H H H H 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 Α 41 41 41 41 41 41 41 41 17 0.935 &lt; 0.11 172 ΕΡ2403832Β1 60)) -NH ζΛ NN 365.08 1.703 OD O: - p;;;; s lt lt lt lt 5 5 5 5 5 5 38 38 38 381,16 1,436 16,0 62 11 NN 390.12 1.572 18 8.8 6 3 Λ 0 H 367.15 1.004 0.948 64 Nííí VPi kAAN-M H 368,14 1,708 0 f 6 8 65 N &quot; fs = N JL JL ^^ Inh o 3¾¾ ^ H 370,16 1,75 2, 0 6 6 Ν Ρ Ρ Ρ Ρ Ρ Ρ H H H H H 382,16 1,126 0,36 173 ΕΡ2403832Β1 67 H - 381.116 1, 148 0.42 68 7 ^ 7 Η 381.16 1, 149 1.4 69? T T T Η Η 385.19 0, 806 41.8 70 νϊ? 7 ν'νί ο Ν'ί: ίνγ ^^ Η 382,16 0,585 0, 15 71 Η 395,18 1, 110 0, 71 η η / ζ. Ν Τ Τ Τ Τ Τ Λ Λ Λ Λ Λ Λ Λ Η Λ Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η 387,19 1, 655 &lt; 0.1 174 ΕΡ2403832Β1 7 5 395.20 1 -; Ο Ch 00 0.1 7 6 Η 382.20 1.159 0.12 Η 383.20 0.859 -L Ο 7 8 Η 370.10 0.888 9 79 ϊΓι rv 450.20 1.251 0.13 80,, - Λ, . & 1ι ην ν 413.20 1,538 0.13 81 F ρ 4 65.2 0 1 f 837 0.2 175 ΕΡ2403832Β1

NMR (DMSO-d 5) δ 1 (Î'), 95 (s, 1H), 8.67 (t, 1H), 8.62 (d, , 1H), 8.49 (d, 1H), 8.09 (d, 2H), 8.02 (d, 1H) ) (M, 2H) F 7.48 - η 4 (m, 1H), 1.55 (m, 1H), 3.84 (s, 2H) ), 2.49 (s, 3H). ΧΗ RK N 400 MH z (DMSO-d 6) δ 10 59 (s, 1H) 8, 78 (d, 1H), 8.56 (m, 1H). 1H), 8.46 (m, 1H), 8.28 (d, 1H), 8.22 (d, 1H), 8.13 (dd, , 7.84-7.81 (m, 2H), 7.17 (m, 1H), 7.70 (m, 1H), 7.47-7.42 (m, 1H) δ 1. 8-7.13 (m, 1H), 3.78 (s, 2H), 29 (s, 3h).

176 ΕΡ2403832Β1 8 6 Jj hn is ist 397.20 1.074 0.38 87 H 382.20 1.428 0.72 88 H 381.2 1.15 0.38 89 H 368.2 1.19 2.8 90 H 427, 1 0.931 0.631 91.4 44.91 1.089 0.3 92 vp Η 4 63.1 1, 052 31 177 ΕΡ2403832Β1 93 Η 4 01.2 0.775 705 94 Η 383.20 0.983 2.1 95 Η 369.2 1.23 1.8 96 Η 382, 1 1.274 2.5 97.JL ^ NF ιΓΐΛ Ν ^ Ν * Τ &gt; Η 387.10 1, 901 98 Η 4 57.2 1,159 99 Η 471.2 1,277 178 ΕΡ2403832Β1 100 °ΑΑ ^ΗΗ 4 83.2 1.280 101Η385.2 0.791 6 612 413.20 1.393 0.23 103 F Η 400.20 1.496 0.59 104 Ν '' 'F 466.20 1.669 0.2 9 105 453.10 1, 94 0 0.11 106 Η 399.2 0.781 19 179 ΕΡ2403832Β1 107 Η 413.2 0.810 35 108 F JL Η 399.2 1.354 0.2 109 Η 369.2 1.74 -! - 110 Η 382.2 1 f 3 6 0.08 111 Η Η Η Η Τι I 1 ΟΝ 455.2 0, 11 112 N J JJ 436.10 1, 915, 1 113 Η 369.20 1.759 0.8 114 Γ Γ Γ J J is is is i i 4 4 4 Η Η Η Η Η Η 386 , 10 1.709 0.6 180 ΕΡ2403832Β1 115 Η 386.10 4,545 - Ό 116 H Q Q X X X X i 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 , 1 118 JAJ N-4 JA t II f Ν Ν 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 7 87 0.1 121 æl nnn F 449.20 1.230 0.1 181 ΕΡ2403832Β1 122 Ν * J * 437.10 1.459 0.2 12 3 FH 399.10 1, 611 0, 9 124 396, 20 0, 94 9 0.2 125 H 488.20 1.408 0.2 12 6 H 382.20 0.947 0.5 &quot; XX H 429.20 0.801 780 128 38.3.20 1.080 0.4 1 H-NMR (DMSO-d 6) δ (CDCl 3) δ (CDCl 3) δ (CDCl 3) 042 0.1 13 3 383.20 1.36 9 0.11 134 Η 383.20 0, 95 8 0.8 135 V9 397.20 2.197 ο% 9 136 397.10 0.918 127 137 Η 383.20 1, 22 0 0, 9 183 ΕΡ2403832Β1

138 H 487.20 1.545 2.7 139 H 383.20 1.221 10.3 140 δ HN 434.20 1.433 4.3 141 H '(Q (H 402.10 0.826 19.514 HaN - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 4 145 W l JIT jl N 397.20 0.950 - r, 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Η 445.20 0.772 - FC '149 Η 458.20 0.990 4.2 150 Η 428.20 1.271 65 151 Η (Χ * ^ μ''λ'ν |, ^ ¾½ kXyN ^ 1 Η 432.20 0.750 163 152 F Η 400.20 1.459 0.3 153 396.20 1.160 0.8 185 ΕΡ2403832Β1 154 »fSSSSSfrfrfrfr 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 413.20 1.027 η λ, ^ 157 ΚΓ ΚΓ ΚΓ ΚΓ 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 4 4 4.2 0 0, 942 0.2 16 0 Λ H 445.20 0.4 62 67 186 ΕΡ2403832Β1 161 Λ γΛ Η 444.20 0.802 45 162 Λ rA Η 444.20 1, 070 1 f \ 1. J 163 Ajl ^ J Λ Η 4 5 9.2 0 0.747 164 XS f * f Η 459.20 0.726 51 165 4 473.20 0.965 14 16 6 h ^ n ^ XfiL χ Η 474.20 1, 818 ο, ι 167 ο κι η || '' ν Η 460.20 1, 161 0.1 168 Λ ^ if &gt; X Ύ Ύ Η 448.10 0.963 Ο, ι 187 ΕΡ2403832Β1 169 Vi AH 431.20 0.479 258 170 VA i Xx'H H 464.10 0.999 0.1 171 H 475.20 1.084 0.2 " ! % Ο Ο Ο Ο Ο. HFF 498.20 1.071 0.1 173 H jl N 405.20 1.250 0.1 174 H 459.20 0.822 0.5 175 h 427.20 1.076 1.1 176 V1 to H 413.20 1.09 7 0.4 188 ΕΡ2403832Β1 -Vi η I Υ 450 450.10 1.433 0.2 178 Λ H 434.20 1.367 0.1 179 N '&quot; 407.20 1.124 0.1 18 0 & A0 407.20 1, 111 0, 1 181 407.20 1036 0.1 182 r &gt; λΟ A 460.20 0.92 8 0.1 183 Λ Ι Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ. 12¾. Ji ^ H 433.20 0.598 0.3 189 ΕΡ2403832Β1 184 [Γΐ> - {465.20 1,046 0.1 185 ΑΑ λ ^ ΥΊί 1 Η 'νΝ 469.20 0 f 126 0.1 18 6 Αί η ^ ΊΤΧ (c) 459.20 0.885! (1) (1) (b) (b) (b) (b) (b) (b) , 1 190 Âμg / cm 2 / ml FH 449.2 0.922 0.2 191 Âμg / kg 462.20 0.97 0 0.04 190 ΕΡ2403832Β1 192 499.20 1.3190, 2 193 NJ 449.20 1.080 0.1 194 Vi a ^ ΝΥΊ] fl H 453.10 1.311 1.3 195 Λπ AH 431.20 1.042 14 196 Λ Λ ^ ^ ^ i i i i i i Λ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ 435.10 1.215 6.7 197 ^ ο λ Jl * H 509.2 0.742 71 198 γΆ 431.20 1.289 63 19 9 H 401.10 1.388 0.2 191 ΕΡ2403832Β1 200 Η 386.10 1.837 0.2 201 Ν 4 66.3 1.339 2.5 202 - (%) 4 66.3 1.43 0 2 03 Οχλ xXJ® ^ Η 418.2 1,860 4.7 204 Α0 s' F Η 449.10 1.239 205 "" 405.20 1, 851 0.1 206 N * &quot; k &quot; K &lt; N * * 411.2 1.888 0.2 207 XQ H 452.2 1,752 0.2 192 ΕΡ2403832Β1 208 Η 387.10 1.683 0.4 209 Η 435.20 1.331 5.4 210 Η 405.10 1.725 0.4 211 4 5 9.2 1.638 0.1 212 Γ ί 4.10 (s, 4H), 4.04 (s, 2H), 2.04 (s, 2H), 2.04 0.1 214 0.01 0.01 0.01 191.2 0.90 19.2 193 213 214 214 214 214.2 218.2 217.22 214.26 326.26 Î »max 422.20 1.444 2.1 217 Hijr 424.20 1.086 6.7 218 rf3 H 425.20 0.272 2.3 219 Â ° F 441.20 0.331 0.8 220Â ° x 38Â ° , 644 0.3 221 H 401.10 1.216 0.3 194 ΕΡ2403832Β1

195 ΕΡ2403832Β1

196 ΕΡ2403832Β1

197 ΕΡ2403832Β1

198 ΕΡ2403832Β1

Essay

Inhibition of

Wnt-Luc Reporter Assay Hangs Wnt Signaling

Mouse leydig TM3 cells (obtained from the American Type Culture Collection, ATCC, Manassas, VA) are cultured in a 1: 1 mixture of Fi: Ham medium and medium of

Lol

Dulbecco's modified Eagle (Gibco / Invitrogen, Carlsbad, CA) supplemented with 2.5% FBS (Gibco / Invitrogen, Carlsbad, CA) and 5% C serum, Manassas, VA; (Gibco / Invitrogen, Carlsbad, CA), 50 units / ml penicillin and 50 mg / ml streptomycin (Gibco / Invitrogen, Carlsbad, CA) at 37 ° C and 5% CO2 in air. TM3 cells on a 10 cm dish are cotransfected with 8 mg of STF reporter plasmid containing a Wnt responding element-driven luciferase gene and 2 mg of pcDNA3.1-Neo (Gibco / Invitrogen, Carlsbad, CA) with 30 ml FuGENE6 (Rocne Diagnostics, Indianapolis, MS) following the manufacturer's protocol. Stable cell lines (TM3 Wnt-Luc) were selected with 400 mg / ml G418 (Gibco / Invitrogen, Carlsbad, CA). Wnt-Luc TM3 cells and Wnt3a cell L cells (obtained from the American Type Culture Collection, ATC in Carlsbad's modified Eagle's medium) supplemented (Gibco / Invitrogen, Carlsbad, CA) penicillin and 50 mg / ml of streptomycin (Gibco / Invitrogen, 199 ΕΡ240383261

Carlsbad, CA) at 37 ° C with 5% CO2 in air) are trypsinized and co-cultured on a 384 well plate with DMEM medium supplemented with 2 Ό FBS and treated with different concentrations of a compound of the formula invention. After 24 hours, firefly luciferase activities are assayed with the ™ Bright Luciferase Assay System (Promega, Madison, WI). The IC50 is measured when the effect of the compound reduces the luminescence signal by 50%.

Reported Wnt-Luc Assay for Wnt Signaling Pathway Inhibition

Human Embryonic Kidney 293 cells (obtained from the American Type Culture Collection, ATCC, Manassas, VA) are grown in DMEM medium (Gibco / Invitrogen, Carlsbad, CA) supplemented with 10% FBS (Gibco / Invitrogen, Carlsbad , CA.), 50 units / ml penicillin and 50 mg / ml streptomycin (Gibco / Invitrogen, Carlsbad, CA) at 37øC with 5% CO 2 under an air atmosphere. The 293 cells on a 10 cm dish are cotransfected with 8 mg of STF reporter plasmid containing a Wnt-responsive element-driven luciferase gene and 2 mg of pcDNA3.1-Neo (Gibco / Invitrogen, Carlsbad, CA) with 30 ml FuGENEd (Roche Diagnostics, Indianapolis, MS) following the manufacturer's protocol. Stable cell lines (293 Wnt-Luc) were selected with 400 mg / ml G418 (Gibco / Invitrogen, Carlsbad, CA). Wnt-Luc 293 cells and Wnt3a cell L cells (obtained from the American Type Culture Collection, ATCC, Manassas, VA) are trypsinized co-cultured on a 384 plate

Wells with DMEM medium supplemented with 2% FBS, and treated with different concentrations of a compound of the invention. After 24 hours, firefly luciferase activities are assayed with the Bright-Glo ™ Luciferase Assay System (Promega, Madison, WI). ICso is measured when the effect of the composite 200 reduces the luminescence signal by 50%.

DOCUMENTS REFERRED TO IN THE DESCRIPTION

This list of documents referred to by the author of the present patent application has been prepared solely for the reader's information. It is not an integral part of the European patent document. Notwithstanding careful preparation, the IEP assumes no responsibility for any errors or omissions.

Patent Documents Referred In Description * US 6602677 B [0125]

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Lisbon, January 16, 2014

Claims (10)

In one embodiment, a pharmaceutically acceptable salt thereof, wherein: wherein X 1, X 3, X 3 and X 4 is selected from N and CR 2; one of X1, X1, X7 and X8 is N and the others are CH; X 9 is selected from N and CH; Z is selected from phenyl, pyrazinyl, pyridinyl, pyridazinyl and piperazinyl; wherein each phenyl, pyrazinyl, pyridinyl, pyridazinyl or piperazinyl of Z is optionally substituted with a group R6; R1, R3 and R3 are hydrogen; m is 1; R4 is selected from hydrogen, halo, difluoromethyl, trifluoromethyl and methyl; R6 is selected from hydrogen, halo and -C (O) R10; wherein R 11 J is methyl; and R? is selected from hydrogen, halo, cyano, methyl and trifluoromethyl. The compound according to claim 1, wherein said compound is selected from 2 ΕΡ2403832Β1 3 ΕΡ2403832Β1 5 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein said compound is 2- (2 ', 3-dimethyl-2, 4'-bipyridin-5-yl) -N- (5- (pyrazin-2-yl ) pyridin-2-yl) acetamide, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein said compound is N- (2,3'-bipyridin-6'-yl) -2- (2 ', 3-dimethyl-2,4'-bipyridin- 5-yl) acetamide, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein said compound is N- (5- (4-acetylpiperazin-1-yl) pyridin-2-yl) -2- (2'-fluoro-3-methyl- 2,4'-bipyridin-5-yl) acetamide, or a pharmaceutically acceptable salt thereof. A compound having the Formula (5): A (5) is: or a pharmaceutically acceptable salt thereof, wherein A1 is piperazinyl substituted with -C (O) CH3, εΡ2403832Β1 Λ s from: ring E is phenyl or one of X 1, X 2, X 3 and X '1 is N and the others are CR'; of X 'Xc X X &quot; : [Z is a 6-membered heterocycle or a 6-membered heteroaryl, each containing 1-2 heteroatoms of nitrogen and each of which is optionally substituted with 1-2 groups R6; R1, R2 and R3 are H; R4 and R6 are independently hydrogen, cyano, C1-6 alkoxy, -S (O) 2 R10, -C (O) NR8 R9, -LC (O) R10, -LC (O) OR10, C1-6 alkyl optionally substituted with halo, alkenyl or C2- and alkynyl; R and n or C ^ -5 archer; L is a bond or (CR2) 1-4 where R is H or C1-6 alkyl; W is C3-7 cycloalkyl; 13 and 21 are independently H, halo, cyano, C1-6 alkoxy, -S (O) 2 R10, or a C1-6 alkyl optionally halogenated; R1 and R9 are independently H, -L-W, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxy, alkoxy or cyano; or R 1 and R 9 together with the atoms to which they are attached may form a ring; R9 is C1-6 alkyl or -L-W; and m, n and p are independently 0-2. The compound according to claim 6 or a pharmaceutically acceptable salt thereof. wherein A1 is piperazinyl substituted with o, S (O) o-2 and m is 0-1. The compound according to any one of claims 6 to 7, wherein said compound is selected from: 15 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 18 ΕΡ2403832Β1 ΕΡ2403832Β1 ΕΡ2403832Β1 or a pharmaceutically acceptable salt thereof. g a. The compound according to any one of claims 6-7, wherein Z is selected from pyrazinyl, pyridinyl, pyridazinyl and piperazinyl; in each pyrazinyl, pyridinyl, pyridazinyl or pyrazole of Z is optionally substituted with a group R6. EP24G3832B1 The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is a fumaric acid salt of said compound. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. Use of a compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of claims 1-10. Claim 11, in the manufacture of a medicament for the treatment of a Wnt-mediated disorder. A compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, for use in a method of treating a Wnt-mediated disorder. The use according to claim 12 or the compound or a pharmaceutically acceptable salt thereof for use in a method of treatment according to claim 13, wherein the Wnt-mediated disorder is fibrotic, proternurie, kidney graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, retinopathy, macular degeneration or a cell proliferation disorder associated with aberrant Wnt signaling activity. substantially in a method of 14, wherein said 1b. The use or the compound or an Acyl acceptable therefor, for the treatment use according to claim 22, is a cell proliferation disorder associated with aberrant Wnt termination cytodiaa and selected from the colorectal cancer group, carcinoma Esophageal cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, pancreatic cancer, leukemia, lymphoma, neuroblasts of the eye, retinoblastoma, sarcoma, osteosarcoma, conaosarcoma, Ewing's sarcoma, rhabdomyosarcoma, cerebellum tumor, Wiim tumor, basal cell carcinoma, melanoma, head and neck cancer, cervical cancer and prostate cancer. The use of a compound according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for the treatment of a treatable disorder by inhibiting Wnt signaling. A compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a subject treated by inhibiting Wnt signaling. Use of a compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of a disorder treatable by inhibition of a porcupine gene. A compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof and for the use thereof in a method of treating a treatable disorder by inhibiting a porcupine gene. jisboa, January 16, 2014 24